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Find video protocols related to scientific articles indexed in Pubmed.
Co-occurrence of congenital hydronephrosis and FOXL2-associated blepharophimosis, ptosis, epicanthus inversus syndrome (BPES).
Eur J Med Genet
PUBLISHED: 09-02-2014
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Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is an autosomal dominantly inherited congenital malformation of the eyelids. Diagnostic criteria include blepharophimosis, ptosis, epicanthus inversus and telecanthus. Type ? BPES has additional features of premature ovarian failure and female infertility, while type ?? occurs isolated. We report a two-year old male child with typical features of BPES and bilateral congenital hydronephrosis. The child, first-born to non-consanguineous parents, presented to us with hypertension. Congenital hydronephrosis and reduced renal function were confirmed by renal dynamic scan. Pyeloplasty and stent placement were performed with subsequent resolution of hypertension. On follow up, growth and development are appropriate for age. His father has similar but less severe features of BPES. Sequencing of the FOXL2 gene revealed a heterozygous FOXL2 mutation c.672_701dup, which is a recurrent 30-bp duplication leading to expansion of the polyalanine tract (p.Ala225_Ala234dup), in both father and son. Additional atypical clinical features have been reported previously in BPES patients with this mutation. However, this is the first report of a renal congenital anomaly in a BPES patient with this or other mutations. Although a pleiotropic effect of the FOXL2 mutation cannot be excluded, the co-occurrence of congenital hydronephrosis and BPES may represent two different entities.
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Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion.
Genet. Med.
PUBLISHED: 08-14-2014
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Purpose:The aim of this study was to identify the genetic cause of early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy in a consanguineous family.Methods:An affected 6-month-old child underwent neurological and ophthalmological examinations. Genetic analyses included homozygosity mapping, copy number analysis, conventional polymerase chain reaction, Sanger sequencing, quantitative polymerase chain reaction, and whole-exome sequencing. Expression analysis of GRID2 was performed by quantitative polymerase chain reaction and immunohistochemistry.Results:A homozygous deletion of exon 2 of GRID2 (p.Gly30_Glu81del) was identified in the proband. GRID2 encodes an ionotropic glutamate receptor known to be selectively expressed in cerebellar Purkinje cells. Here, we demonstrated GRID2 expression in human adult retina and retinal pigment epithelium. In addition, Grid2 expression was demonstrated in different stages of murine retinal development. GRID2 immunostaining was shown in murine and human retina. Whole-exome sequencing in the proband did not provide arguments for other disease-causing mutations, supporting the idea that the phenotype observed represents a single clinical entity.Conclusion:We identified GRID2 as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy, expanding the clinical spectrum of GRID2 deletion mutants. We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina.Genet Med advance online publication 14 August 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.95.
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An Augmented ABCA4 Screen Targeting Non-coding Regions Reveals a Deep Intronic Founder Variant in Belgian Stargardt Patients.
Hum. Mutat.
PUBLISHED: 07-30-2014
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Autosomal recessive Stargardt disease (STGD1) is hallmarked by a large proportion of patients with a single heterozygous causative variant in the disease gene ABCA4. Braun et al. (2013) reported deep intronic variants of ABCA4 in STGD1 patients with one coding variant, prompting us to perform an augmented screen in 131 Belgian STGD1 patients with one or no ABCA4 variant to uncover deep intronic causal ABCA4 variants. This revealed a second variant in 28.6% of cases. Twenty-six percent of these carry the same causal variant c.4539+2001G>A (V4). Haplotyping in V4 carriers showed a common region of 63 kb, suggestive of a founder mutation. Genotype-phenotype correlations suggest a moderate-to-severe impact of V4 on the STGD1 phenotype. In conclusion, V4 occurs in a high fraction of Belgian STGD1 patients and represents the first deep intronic founder mutation in ABCA4. This emphasizes the importance of augmented molecular genetic testing of ABCA4 in Belgian STGD1. This article is protected by copyright. All rights reserved.
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De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation.
Hum. Genet.
PUBLISHED: 04-21-2014
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Xq28 microduplications of MECP2 are a prominent cause of a severe syndromic form of intellectual disability (ID) in males. Females are usually unaffected through near to complete X-inactivation of the aberrant X chromosome (skewing). In rare cases, affected females have been described due to random X-inactivation. Here, we report on two female patients carrying de novo MECP2 microduplications on their fully active X chromosomes. Both patients present with ID and additional clinical features. Mono-allelic expression confirmed complete skewing of X-inactivation. Consequently, significantly enhanced MECP2 mRNA levels were observed. We hypothesize that the cause for the complete skewing is due to a more harmful mutation on the other X chromosome, thereby forcing the MECP2 duplication to become active. However, we could not unequivocally identify such a second mutation by array-CGH or exome sequencing. Our data underline that, like in males, increased MECP2 dosage in females can contribute to ID too, which should be taken into account in diagnostics.
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A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma.
J. Med. Genet.
PUBLISHED: 04-15-2014
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Retinitis pigmentosa (RP) is the most frequent inherited retinal disease, which shows a relatively high incidence of the autosomal-recessive form in Pakistan.
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Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics.
Orphanet J Rare Dis
PUBLISHED: 02-10-2014
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Congenital cataracts are clinically and genetically heterogeneous with more than 45 known loci and 38 identified genes. They can occur as isolated defects or in association with anterior segment developmental anomalies. One of the disease genes for congenital cataract with or without anterior segment dysgenesis (ASD) is PITX3, encoding a transcription factor with a crucial role in lens and anterior segment development. Only five unique PITX3 mutations have been described, of which the 17-bp duplication c.640_656dup, p.(Gly220Profs*95), is the most common one and the only one known to cause cataract with ASD. The aim of this study was to perform a genetic study of the PITX3 gene in five probands with autosomal dominant congenital cataract (ADCC) and ASD, to compare their clinical presentations to previously reported PITX3-associated phenotypes and to functionally evaluate the PITX3 mutations found.
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Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy.
Genet. Med.
PUBLISHED: 02-05-2014
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Autosomal recessive retinal dystrophies are clinically and genetically heterogeneous, which hampers molecular diagnosis. We evaluated identity-by-descent-guided Sanger sequencing or whole-exome sequencing in 26 families with nonsyndromic (19) or syndromic (7) autosomal recessive retinal dystrophies to identify disease-causing mutations.
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Structural and numerical changes of chromosome X in patients with esophageal atresia.
Eur. J. Hum. Genet.
PUBLISHED: 01-08-2014
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Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a relatively common birth defect often associated with additional congenital anomalies such as vertebral, anal, cardiovascular, renal and limb defects, the so-called VACTERL association. Yet, little is known about the causal genetic factors. Rare case reports of gastrointestinal anomalies in children with triple X syndrome prompted us to survey the incidence of structural and numerical changes of chromosome X in patients with EA/TEF. All available (n=269) karyotypes of our large (321) EA/TEF patient cohort were evaluated for X-chromosome anomalies. If sufficient DNA material was available, we determined genome-wide copy number profiles with SNP array and identified subtelomeric aberrations on the difficult to profile PAR1 region using telomere-multiplex ligation-dependent probe amplification. In addition, we investigated X-chromosome inactivation (XCI) patterns and mode of inheritance of detected aberrations in selected patients. Three EA/TEF patients had an additional maternally inherited X chromosome. These three female patients had normal random XCI patterns. Two male EA/TEF patients had small inherited duplications of the XY-linked SHOX (Short stature HOmeoboX-containing) locus. Patients were small for gestational age at birth (
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High-resolution optical coherence tomography, autofluorescence, and infrared reflectance imaging in Sjögren reticular dystrophy.
Retina (Philadelphia, Pa.)
PUBLISHED: 04-27-2013
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To describe the phenotype of three cases of Sjögren reticular dystrophy in detail, including high-resolution optical coherence tomography, autofluorescence imaging, and near-infrared reflectance imaging.
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Mutations in IMPG1 cause vitelliform macular dystrophies.
Am. J. Hum. Genet.
PUBLISHED: 04-06-2013
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Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507(?)). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.
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Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations.
Hum. Mutat.
PUBLISHED: 03-29-2013
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This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ?2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
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Maternal uniparental isodisomy of chromosome 6 reveals a TULP1 mutation as a novel cause of cone dysfunction.
Ophthalmology
PUBLISHED: 03-15-2013
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The majority of the genetic causes of autosomal recessive (ar) cone dystrophy (CD) and cone-rod dystrophy (CRD) are currently unknown. We used a high-resolution homozygosity mapping approach in a cohort of patients with CD or CRD to identify new genes for ar cone disorders.
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Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain.
PLoS Genet.
PUBLISHED: 01-18-2013
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Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms--such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)--were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease.
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Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies.
Hum. Mol. Genet.
PUBLISHED: 01-09-2013
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Retinal dystrophies are predominantly caused by mutations affecting the visual phototransduction system and cilia, with few genes identified that function to maintain photoreceptor survival. We reasoned that growth factors involved with early embryonic retinal development would represent excellent candidates for such diseases. Here we show that mutations in the transforming growth factor-? (TGF-?) ligand Growth Differentiation Factor 6, which specifies the dorso-ventral retinal axis, contribute to Leber congenital amaurosis. Furthermore, deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. In addition, in both murine and zebrafish mutant models, we observe retinal apoptosis, a characteristic feature of human retinal dystrophies. Treatment of gdf6-deficient zebrafish embryos with a novel aminopropyl carbazole, P7C3, rescued the retinal apoptosis without evidence of toxicity. These findings implicate for the first time perturbed TGF-? signaling in the genesis of retinal dystrophies, support the study of related morphogenetic genes for comparable roles in retinal disease and may offer additional therapeutic opportunities for genetically heterogeneous disorders presently only treatable with gene therapy.
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Insights into levator muscle dysfunction in a cohort of patients with molecularly confirmed blepharophimosis-ptosis-epicanthus inversus syndrome using high-resolution imaging, anatomic examination, and histopathologic examination.
Arch. Ophthalmol.
PUBLISHED: 12-14-2011
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To study the basis of defective levator palpebrae superioris (LPS) function in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), an autosomal dominant eyelid malformation sometimes associated with ovarian dysfunction.
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Gender identity disorder in twins: a review of the case report literature.
J Sex Med
PUBLISHED: 12-06-2011
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The etiology of gender identity disorder (GID) remains largely unknown. In recent literature, increased attention has been attributed to possible biological factors in addition to psychological variables.
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Increased levator muscle function by supramaximal resection in patients with blepharophimosis-ptosis-epicanthus inversus syndrome.
Arch. Ophthalmol.
PUBLISHED: 08-10-2011
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To study the efficacy and clinical and anatomical results of supramaximal levator resection in patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) with severe congenital ptosis with poor levator function (LF).
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Nonsyndromic bilateral and unilateral optic nerve aplasia: first familial occurrence and potential implication of CYP26A1 and CYP26C1 genes.
Mol. Vis.
PUBLISHED: 08-02-2011
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Optic nerve aplasia (ONA, OMIM 165550) is a very rare unilateral or bilateral condition that leads to blindness in the affected eye, and is usually associated with other ocular abnormalities. Although bilateral ONA often occurs in association with severe congenital anomalies of the brain, nonsyndromic sporadic forms with bilateral ONA have been described. So far, no autosomal-dominant nonsyndromic ONA has been reported. The genetic basis of this condition remains largely unknown, as no developmental genes other than paired box gene 6 (PAX6) are known to be implicated in sporadic bilateral ONA.
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Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response.
Hum. Mutat.
PUBLISHED: 07-11-2011
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Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations are present in a substantial fraction (2.2-4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel. A new finding of this study is the substantial proportion of large deletions at the KCNV2 locus that accounts for 15.5% of the mutant alleles in our sample. We determined the breakpoints and size of all five different deletions, which ranged between 10.9 and 236.8 kb. Two deletions encompass the entire KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack of assembly of heteromeric Kv channels as one underlying pathomechanism of CDSRR.
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Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.
PLoS Genet.
PUBLISHED: 05-25-2011
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The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P?=?2.32×10(-12), OR?=?0.75). Also, rs12540874 in GRB10 gene (P?=?1.27 × 10(-6), OR?=?1.15) and rs11047102 in SOX5 gene (P?=?1.39×10(-7), OR?=?1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P?=?1.79×10(-61), OR?=?2.48), in the HLA-DPA1/B1 loci with ATA (P?=?4.57×10(-76), OR?=?8.84), and in NOTCH4 with ACA P?=?8.84×10(-21), OR?=?0.55) and ATA (P?=?1.14×10(-8), OR?=?0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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Correction of the lower eyelid malpositioning in the blepharophimosis-ptosis-epicanthus inversus syndrome.
Ophthal Plast Reconstr Surg
PUBLISHED: 05-13-2011
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Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant complex eyelid malformation. The authors aim to offer an explanation for the lower eyelid malformation and propose a novel surgical approach to correct it.
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Discordance for retinitis pigmentosa in two monozygotic twin pairs.
Retina (Philadelphia, Pa.)
PUBLISHED: 02-02-2011
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Retinitis pigmentosa (RP) is a group of genetically heterogeneous diseases with progressive degeneration of the retina. The condition can be inherited as an autosomal dominant, autosomal recessive, and X-linked trait.
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IQCB1 mutations in patients with leber congenital amaurosis.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 01-01-2011
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Leber congenital amaurosis (LCA) is genetically heterogeneous, with 15 genes identified thus far, accounting for ?70% of LCA patients. The aim of the present study was to identify new genetic causes of LCA.
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Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 01-01-2011
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Anterior segment dysgenesis (ASD) comprises a heterogeneous group of developmental abnormalities that affect several structures of the anterior segment of the eye. The main purpose of this study was to assess the proportion of FOXC1 and PITX2 mutations and copy number changes in 80 probands with ASD.
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CEP290, a gene with many faces: mutation overview and presentation of CEP290base.
Hum. Mutat.
PUBLISHED: 08-07-2010
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Ciliopathies are an emerging group of disorders, caused by mutations in ciliary genes. One of the most intriguing disease genes associated with ciliopathies is CEP290, in which mutations cause a wide variety of distinct phenotypes, ranging from isolated blindness over Senior-Loken syndrome (SLS), nephronophthisis (NPHP), Joubert syndrome (related disorders) (JS[RD]), Bardet-Biedl syndrome (BBS), to the lethal Meckel-Grüber syndrome (MKS). Despite the identification of over 100 unique CEP290 mutations, no clear genotype-phenotype correlations could yet be established, and consequently the predictive power of a CEP290-related genotype remains limited. One of the challenges is a better understanding of second-site modifiers. In this respect, there is a growing interest in the potential modifying effects of variations in genes encoding other members of the ciliary proteome that interact with CEP290. Here, we provide an overview of all CEP290 mutations identified so far, with their associated phenotypes. To this end, we developed CEP290base, a locus-specific mutation database that links mutations with patients and their phenotypes (medgen.ugent.be/cep290base).
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Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes.
Hum. Mutat.
PUBLISHED: 08-05-2010
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Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease.
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Improved molecular diagnostics of idiopathic short stature and allied disorders: quantitative polymerase chain reaction-based copy number profiling of SHOX and pseudoautosomal region 1.
J. Clin. Endocrinol. Metab.
PUBLISHED: 04-07-2010
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Short stature has an incidence of three in 100 in children. Reliable molecular genetic testing may be crucial in the context of beneficial disease management. Deletions spanning or surrounding the SHOX gene account for a significant proportion of patients with idiopathic short stature (ISS) and allied disorders, such as Leri-Weill dyschondrosteosis.
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Functional exploration of the adult ovarian granulosa cell tumor-associated somatic FOXL2 mutation p.Cys134Trp (c.402C>G).
PLoS ONE
PUBLISHED: 01-20-2010
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The somatic mutation in the FOXL2 gene c.402C>G (p.Cys134Trp) has recently been identified in the vast majority of adult ovarian granulosa cell tumors (OGCTs) studied. In addition, this mutation seems to be specific to adult OGCTs and is likely to be a driver of malignant transformation. However, its pathogenic mechanisms remain elusive.
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Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.
Nat. Genet.
PUBLISHED: 01-04-2010
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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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Autosomal dominant syndrome of mental retardation, hypotelorism, and cleft palate resembling Schilbach-Rott syndrome.
Am. J. Med. Genet. A
PUBLISHED: 11-19-2009
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We present a family segregating for an autosomal dominant syndrome of hypotelorism, cleft palate/uvula, high-arched palate and mild mental retardation. Although these findings may suggest a form of holoprosencephaly, no holoprosencephaly was found on MRI of the proposita. Results of genetic studies were normal including FISH for deletion of 22q11, karyotype analysis, fragile X testing, high-resolution comparative genomic hybridization and SEPT9, SHH mutation analysis. The syndrome is reminiscent of the infrequently recognized autosomal dominant Schilbach-Rott syndrome.
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Age-dependent effects of RPE65 gene therapy for Lebers congenital amaurosis: a phase 1 dose-escalation trial.
Lancet
PUBLISHED: 10-23-2009
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Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Lebers congenital amaurosis.
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FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report.
Hum. Reprod.
PUBLISHED: 10-09-2009
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FOXL2 mutations cause the autosomal dominant Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) that may be associated with premature ovarian failure (POF). However, little is known about the molecular mechanisms of FOXL2 actions in the human ovary. We conducted an extensive clinical, hormonal and ovarian histological study in two patients carrying a FOXL2 mutation associated with the typical eyelid malformations and infertility. This observational study was conducted at referral centres for POF. Histological and immunohistological studies were conducted on ovarian biopsies from two women with POF carrying a FOXL2 mutation resulting in putative polyalanine expansions of the protein. Abnormalities similar to those observed in mice with FOXL2 gene inactivation were present in the first patients ovary, although the ovarian histology of the second patient was apparently normal. Different ovarian phenotypes, follicular defects and distribution of FOXL2 protein were observed in two patients carrying a FOXL2 mutation.
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The transcription factor FOXL2 in ovarian function and dysfunction.
Folia Histochem. Cytobiol.
PUBLISHED: 10-01-2009
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The Blepharophimosis Ptosis Epicanthus-inversus Syndrome is a genetic disease characterized by complex eyelid malformations often associated with premature ovarian failure (POF). BPES is basically an autosomal dominant disease, due to mutations in the FOXL2 gene, which encodes a forkhead transcription factor. More than one hundred mutations of FOXL2 have been described to date. In agreement with the BPES phenotype, FOXL2 is expressed (though not exclusively) in the developing eyelids and in fetal and adult ovaries. Two mouse knock-out models have been produced. They recapitulate the BPES phenotype and have provided insights into the pathology. Loss-of-function mutations in FOXL2 are predicted to lead to BPES and POF, while hypomorphic mutations might lead to BPES without ovarian dysfunction. However, exceptions to the genotype-phenotype correlation have been described. To better understand the pathogenic effect of these mutations it is crucial to study the normal regulation of FOXL2 and its targets. We briefly address these aspects in this review and hope that basic research around FOXL2 will eventually lead to uncover new therapeutic avenues.
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TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness.
Am. J. Hum. Genet.
PUBLISHED: 09-25-2009
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Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in approximately 60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells.
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Genotyping microarray for CSNB-associated genes.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 07-02-2009
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Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disease. Although electroretinographic (ERG) measurements can discriminate clinical subgroups, the identification of the underlying genetic defects has been complicated for CSNB because of genetic heterogeneity, the uncertainty about the mode of inheritance, and time-consuming and costly mutation scanning and direct sequencing approaches.
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Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders.
Am. J. Hum. Genet.
PUBLISHED: 04-24-2009
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Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.
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FOXL2 mutations and genomic rearrangements in BPES.
Hum. Mutat.
PUBLISHED: 04-11-2009
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The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (POF). In addition, a few mutations have been described in patients with isolated POF. Here, we review all currently described FOXL2 sequence variations and genomic rearrangements in BPES and POF. Using a combined mutation detection approach, it is possible to identify the underlying genetic defect in a major proportion (88%) of typical BPES patients. Of all genetic defects found in our BPES cohort, intragenic mutations represent 81%. They include missense changes, frameshift and nonsense mutations, in-frame deletions, and duplications, that are distributed along the single-exon gene. Genomic rearrangements comprising both deletions encompassing FOXL2 and deletions located outside its transcription unit, represent 12% and 5% of all genetic defects in our BPES cohort, respectively. One of the challenges of genetic testing in BPES is the establishment of genotype-phenotype correlations, mainly with respect to the ovarian phenotype. Genetic testing should be performed in the context of genetic counseling, however, and should be systematically complemented by a multidisciplinary clinical follow-up. Another challenge for health care professionals involved in BPES is the treatment of the eyelid phenotype and the prevention or treatment of POF.
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Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations.
Hum. Mol. Genet.
PUBLISHED: 02-28-2009
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FOXL2 is a forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the blepharophimosis syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial manganese superoxide dismutase (MnSOD). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of FOXL2 induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene MnSOD. Taken together, our results establish that FOXL2 is an actor of the stress response and provide new insights into the pathogenic consequences of FOXL2 mutations.
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Peculiar fundus abnormalities and pathognomonic electrophysiological findings in a 14-month-old boy with NR2E3 mutations.
Ophthalmic Genet.
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Enhanced S-cone syndrome is a rare, slowly progressive autosomal recessively inherited retinal degeneration related to mutations in the NR2E3 gene. Patients often present with night blindness, visual loss and visual field abnormalities. Patients with enhanced S-cone syndrome exhibit a variable clinical phenotype associated with various degrees of pigmentary changes and foveal schisis. We report a 14-month-old boy with an unusual funduscopic appearance. The diagnosis of enhanced S-cone syndrome was suggested by the uniquely abnormal electroretinographic pattern and was confirmed by the finding of homozygous NR2E3 mutations.
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A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia.
Am. J. Hum. Genet.
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Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM, and all encode functional components of the phototransduction cascade in cone photoreceptors. Applying a functional-candidate-gene approach that focused on screening additional genes involved in this process in a cohort of 611 index cases with ACHM or other cone photoreceptor disorders, we detected a homozygous single base change (c.35C>G) resulting in a nonsense mutation (p.Ser12(?)) in PDE6H, encoding the inhibitory ? subunit of the cone photoreceptor cyclic guanosine monophosphate phosphodiesterase. The c.35C>G mutation was present in three individuals from two independent families with a clinical diagnosis of incomplete ACHM and preserved short-wavelength-sensitive cone function. Moreover, we show through immunohistochemical colocalization studies in mouse retina that Pde6h is evenly present in all retinal cone photoreceptors, a fact that had been under debate in the past. These findings add PDE6H to the set of genes involved in autosomal-recessive cone disorders and demonstrate the importance of the inhibitory ? subunit in cone phototransduction.
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HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.
Nature
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Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion and also has key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.
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TMEM126A mutation in a Moroccan family with autosomal recessive optic atrophy.
Mol. Vis.
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Nonsyndromic autosomal recessive optic atrophy (arOA) is extremely rare and its existence was disputed until a locus, optic atrophy 6 (OPA6), was mapped to 8q. Recently, a second locus, OPA7, was found on 11q in several families from North Africa, with one presumably ancestral mutation of transmembrane protein 126A (TMEM126A). Here we report an independently ascertained large consanguineous family of Moroccan descent with three siblings affected with nonsyndromic arOA.
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Enhanced S-cone syndrome with preserved macular structure and severely depressed retinal function.
Doc Ophthalmol
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We present ophthalmic features and genetic analysis findings of a 44-year-old croatian patient with enhanced S-cone syndrome (ESCS). Complete ophthalmic examination, Ishihara colour vision test, dark adaptometry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, Goldmann visual field and automated perimetry, full-field electroretinography (ERG), multifocal ERG, S-cone ERG and ON-OFF ERG were performed. Mutation screening of the NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed with polymerase chain reaction amplification and direct sequencing. The patient has good visual acuity and normal colour vision. Fundus examination showed normal posterior pole and nummular pigment depositions at the level of the retinal pigment epithelium in the mid-periphery of the retina. The SD-OCT images showed normal macular structure and thickness. The ERG showed characteristic findings: photopic and scotopic responses to the same stimulus had a similar waveform and were dominated by short-wavelength-sensitive mechanisms. Mutation analysis revealed the known NR2E3 mutation c.481delA (p.Thr161HisFsX18) and the novel NR2E3 variant c.1120C > T (p.Leu374Phe). To the best of our knowledge, this is the only ESCS patient older than 40 years who phenotypically has preserved macular structure, good central visual acuity and severely depressed full-field ERG as well as the first reported patient with NR2E3 mutation from Croatia.
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Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation.
Am. J. Hum. Genet.
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Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.
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Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.
Am. J. Hum. Genet.
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Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(?)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.
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Missense mutation outside the forkhead domain of FOXL2 causes a severe form of BPES type II.
Mol. Vis.
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Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a developmental disease characterized by a complex eyelid malformation associated or not with premature ovarian failure (POF). BPES is essentially an autosomal dominant disease, due to mutations in the forkhead box L2 (FOXL2) gene, encoding a forkhead transcription factor. More than one hundred unique FOXL2 mutations have been described in BPES in different populations, many of which are missense mutations in the forkhead domain. Here, we report on a very severe form of BPES resulting from a missense mutation outside the forkhead domain.
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Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis.
Genet. Med.
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Leber congenital amaurosis (LCA) is a rare congenital retinal dystrophy associated with 16 genes. Recent breakthroughs in LCA gene therapy offer the first prospect of treating inherited blindness, which requires an unequivocal and early molecular diagnosis. While present genetic tests do not address this due to a tremendous genetic heterogeneity, massively parallel sequencing (MPS) strategies might bring a solution. Here, we developed a comprehensive molecular test for LCA based on targeted MPS of all exons of 16 known LCA genes.
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FOXL2 impairment in human disease.
Horm Res Paediatr
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FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome.
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