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Find video protocols related to scientific articles indexed in Pubmed.
Aggressive primary olfactory neuroblastoma of the sphenoclival region: A case report and literature review.
Laryngoscope
PUBLISHED: 07-07-2014
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Olfactory neuroblastoma (ONB) is an uncommon malignant tumor of neural crest origin, which commonly arises in the superior nasal cavity. Ectopic origin of an ONB is exceedingly rare. We describe a rare case of an ectopic sphenoclival ONB with extensive involvement of the central skull base and with development of systemic metastases. To our knowledge, ours is the first case that describes the imaging features of this rare entity on computed tomography (CT), magnetic resonance imaging, 18 F-fluorodeoxyglucose-positron-emission tomography/CT, and digital subtraction angiography. We also describe the histological features, imaging differentials, and treatment options for this tumor along with a brief literature review.
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Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies.
Hum. Mutat.
PUBLISHED: 06-14-2014
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A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (?7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease. This article is protected by copyright. All rights reserved.
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Mosaicism for Dominant Collagen VI Mutations as a Cause for Intra-Familial Phenotypic Variability.
Hum. Mutat.
PUBLISHED: 04-18-2014
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Collagen VI-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy (UCMD), intermediate phenotypes, to the milder Bethlem myopathy (BM). Both inter- and intra-familial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked inter-generational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional 5(th) simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2 and COL6A3) in genomic DNA (gDNA) from various tissues; including blood, saliva, and dermal fibroblasts. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared to the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intra-familial/inter-generational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected. This article is protected by copyright. All rights reserved.
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Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly.
J. Med. Genet.
PUBLISHED: 04-17-2014
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Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly.
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Novel ANO5 homozygous microdeletion causing myalgia and unprovoked rhabdomyolysis in an Arabic man.
Muscle Nerve
PUBLISHED: 04-09-2014
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Recessive mutations in the anoctamin-5 gene (ANO5) cause a spectrum of clinical phenotypes, including limb-girdle muscular dystrophy (LGMD 2L), distal myopathy, and asymptomatic hyperCKemia.
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Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations.
J. Neuropathol. Exp. Neurol.
PUBLISHED: 04-09-2014
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Dystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on ?-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic acid, allowing ?-dystroglycan to bind ligands, including laminin 211 and neurexin. Only 11 patients with LARGE mutations have been reported. We report the clinical, neuroimaging, and genetic features of 4 additional patients. We confirm that gross deletions and rearrangements are important mutational mechanisms for LARGE. The brain abnormalities overshadowed the initially mild muscle phenotype in all 4 patients. We present the first comprehensive postnatal neuropathology of the brain, spinal cord, and eyes of a patient with a homozygous LARGE mutation at Cys443. In this patient, polymicrogyria was the predominant cortical malformation; densely festooned polymicrogyria were overlaid by a continuous agyric surface. In view of the severity of these abnormalities, Cys443 may be a functionally important residue in the LARGE protein, whereas the mutation p.Glu509Lys of Patient 1 in this study may confer a milder phenotype. Overall, these results expand the clinical and genetic spectrum of dystroglycanopathy.
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Targeted therapy in advanced metastatic colorectal cancer: current concepts and perspectives.
World J. Gastroenterol.
PUBLISHED: 02-20-2014
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The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I?and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.
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A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients.
Clin. Cancer Res.
PUBLISHED: 01-27-2014
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Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma.
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Significant survival impact of MACC1 polymorphisms in HER2 positive breast cancer patients.
Eur. J. Cancer
PUBLISHED: 01-08-2014
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Deregulation of hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signalling has been associated with poor clinical outcome in breast cancer and other cancers. The recently discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Potential links between genetic variants of the MACC1 gene and survival in breast cancer patients are unknown. In the present study, we therefore aimed to investigate the influence of MACC1 polymorphisms on event-free and overall survival in patients with human epidermal growth factor 2 (HER2)-positive breast cancer.
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A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations.
Neuromuscul. Disord.
PUBLISHED: 01-03-2014
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Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles.
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Plastin polymorphisms predict gender and stage-specific colon cancer recurrence after adjuvant chemotherapy.
Mol. Cancer Ther.
PUBLISHED: 10-29-2013
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Tumor recurrence after curative resection remains a major problem in patients with locally advanced colorectal cancer (CRC) treated with adjuvant chemotherapy. Genetic single nucleotide polymorphisms (SNPs) may serve as useful molecular markers to predict clinical outcomes in these patients and identify targets for future drug development. Recent in vitro and in vivo studies have demonstrated that the plastin genes, PLS3 and LCP1, are overexpressed in colon cancer cells and play an important role in tumor cell invasion, adhesion and migration. Hence, we hypothesized that functional genetic variations of plastin may direct effects on the progression and prognosis of locally advanced CRC. We tested whether functional tagging polymorphisms of PLS3 and LCP1 predict time to tumor recurrence (TTR) in 732 patients (training set: 234; validation set: 498) with stage II/III CRC. The PLS3 rs11342 and LCP1 rs4941543 polymorphisms were associated with a significantly increased risk for recurrence in the training set. PLS3 rs6643869 showed a consistent association with TTR in the training and validation set, when stratified by gender and tumor location. Female patients with the PLS3 rs6643869 AA genotype had the shortest median TTR compared to those with any G allele in the training set [1.7 vs. 9.4 years; HR 2.84(95% CI=1.32-6.1); p=0.005] and validation set [3.3 vs. 13.7 years; HR 2.07 (95%CI=1.09-3.91); p=0.021]. Our findings suggest that several SNPs of the PLS3 and LCP1 genes could serve as gender and/or stage-specific molecular predictors of tumor recurrence in stage II/III CRC patients as well as potential therapeutic targets.
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Severe congenital RYR1-associated myopathy: the expanding clinicopathologic and genetic spectrum.
Neurology
PUBLISHED: 04-03-2013
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To report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene-related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients.
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Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies.
Hum. Mutat.
PUBLISHED: 02-27-2013
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Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix.
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A common and functional gene variant in the vascular endothelial growth factor a predicts clinical outcome in early-stage breast cancer.
Mol. Carcinog.
PUBLISHED: 02-25-2013
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Angiogenesis and cell cycle control play critical roles in breast cancer susceptibility and clinical outcome and are mainly controlled by vascular endothelial growth factor (VEGF) and cyclin-dependent kinases, respectively. Functional germline polymorphisms in these genes alter the function, thereby causing inter-individual differences in breast cancer risk and clinical outcome. In this study, we investigated the influence of the functional polymorphisms VEGF-A rs3025039 C > T and CCND1 rs9344 G > A on risk and clinical outcome in early-stage breast cancer. DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 control subjects was genotyped for these polymorphisms. Genotypes were tested for associations with breast cancer risk and clinical outcome. There was no significant association between the polymorphisms and breast cancer risk. However, the minor allele of VEGF-A rs3025039 C > T was significantly associated with decreased recurrence-free survival (HR 1.845; 95% confidence interval [CI] 1.035-3.290; P = 0.038) and remained significant in multivariate analysis (HR 1.880; 95% CI 1.020-3.465; P = 0.043). Patients carrying at least one A-allele in CCND1 rs9344 G > A showed a trend towards decreased recurrence-free survival in univariate analysis (HR 2.379; 95% CI 0.841-6.728; P = 0.068). This study provides evidence that the functional VEGF-A rs3025039 C > T polymorphism influences recurrence-free survival in early-stage breast cancer.
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Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.
Brain
PUBLISHED: 02-16-2013
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The ?-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and ?-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of ?-tropomyosin-related myopathies through the identification of a novel ?-tropomyosin mutation in two clinical contexts not previously associated with ?-tropomyosin. The first clinical phenotype is core-rod myopathy, with a ?-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of ?-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the ?-helices of dimeric ?-tropomyosin, a change predicted to alter protein-protein binding between ?-tropomyosin and other molecules and to disturb head-to-tail polymerization of ?-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del ?-tropomyosin in the developing zebrafish. p.K7del ?-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail ?-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel ?-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with ?-tropomyosin and pathogenic data from the first animal model of ?-tropomyosin-related myopathies.
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A common gene variant in PLS3 predicts colon cancer recurrence in women.
Tumour Biol.
PUBLISHED: 01-20-2013
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Recent evidence suggests that PLS3 (T-Plastin), an important member of the actin filamentous network, significantly influences cell invasion and metastasis. Germline polymorphisms within the PLS3 gene may impact the genes function, resulting in inter-individual differences in tumor recurrence capacity. In the present study, we investigated the association of germline polymorphisms in PLS3 to predict time to recurrence (TTR) in patients with stage II and III colon cancer. A total of 264 patients with histologically confirmed colon cancer were included in this retrospective study. Germline DNA was genotyped for rs871773 C>T, rs757124 C>G, rs1557770 G>T, rs6643869 G>A, and rs2522188 C>T in the PLS3 gene by 5-exonuclease (TaqMan™) technology. As the PLS3 gene is located on the X chromosome, a gender-specific statistical analysis was performed. In univariate analysis, the minor allele of PLS3 rs871773 C>T was significantly associated with decreased TTR in women (hazard ratio (HR) = 5.02; 95 % confidence interval (CI) = 1.251-20.114; p = 0.023) and remained significantly associated in multivariate analysis (HR = 6.165; 95 % CI = 1.538-24.716; p = 0.010). Female patients carrying the C/T genotype in PLS3 rs871773 showed a median TTR of 69 months. In contrast, female patients with homozygous C/C had a median TTR of 112 months. There were no significant associations between PLS3 rs871773 C>T and TTR in male and between the other polymorphisms and TTR in male or female colon cancer patients. In conclusion, we identified a common gene variant in PLS3 as an independent prognostic marker in female patients with stage II and III colon cancer. Larger prospective trials are warranted to confirm these findings.
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Common cancer stem cell gene variants predict colon cancer recurrence.
Clin. Cancer Res.
PUBLISHED: 09-14-2011
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Recent evidence suggests that cancer stem cells (CSC) are responsible for key elements of colon cancer progression and recurrence. Germline variants in CSC genes may result in altered gene function and/or activity, thereby causing interindividual differences in a patients tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer.
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Predictive molecular classifiers in colorectal cancer.
Semin. Oncol.
PUBLISHED: 08-04-2011
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The introduction of predictive molecular markers has radically enhanced the identification of which patients may benefit from a given treatment. Despite recent controversies, KRAS mutation is currently the most recognized molecular predictive marker in colorectal cancer (CRC), predicting efficacy of anti-epidermal growth factor receptor (anti-EGFR) antibodies. However, other relevant markers have been reported and claimed to identify patients that will benefit from anti-EGFR therapies. This group of markers includes BRAF mutations, PI3KCA mutations, and loss of PTEN expression. Similarly, molecular markers for cytotoxic agents efficacy also may predict outcome in patients with CRC. This review aims to summarize the most important predictive molecular classifiers in patients with CRC and further discuss any inconsistent or conflicting findings for these molecular classifiers.
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Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
Clin. Cancer Res.
PUBLISHED: 07-26-2011
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There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.
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Amyloidosis and exercise intolerance in ANO5 muscular dystrophy.
Neuromuscul. Disord.
PUBLISHED: 05-10-2011
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Anoctamin 5 and dysferlin mutations can result in myopathies with similar clinical phenotype. Amyloid deposits can occur in the muscle of patients with dysferlinopathy. We describe a 53-year-old woman with exercise intolerance since childhood, recurrent rhabdomyolysis and late-onset weakness. Muscle biopsy showed amyloid deposits within the blood vessel walls and around muscle fibers. Mutation analysis identified two pathogenic heterozygous mutations in anoctamin 5 and no mutations in dysferlin. To our knowledge this is the first report of muscle amyloidosis in anoctamin 5 muscular dystrophy. This finding suggests that patients with amyloid in muscle should be screened for anoctamin 5 muscular dystrophy.
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Holoprosencephaly in a family segregating novel variants in ZIC2 and GLI2.
Am. J. Med. Genet. A
PUBLISHED: 03-17-2011
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Holoprosencephaly (HPE) is the most common malformation of the human forebrain. Typical manifestations in affected patients include a characteristic pattern of structural brain and craniofacial anomalies. HPE may be caused by mutations in over 10 identified genes; the inheritance is traditionally viewed as autosomal dominant with highly variable expressivity and incomplete penetrance. We present the description of a family simultaneously segregating two novel variants in the HPE-associated genes, ZIC2 and GLI2, as well as the results of extensive population-based studies of the variant region in GLI2. This is the first time that multiple HPE-associated variants in these genes have been reported in one family, and raises important questions about how clinicians and researchers should view the inheritance of conditions such as HPE.
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Single nucleotide polymorphisms of TCF7L2 are linked to diabetic coronary atherosclerosis.
PLoS ONE
PUBLISHED: 02-20-2011
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Coronary artery disease (CAD) shares common risk factors with type 2 diabetes (T2DM). Variations in the transcription factor 7-like 2 (TCF7L2) gene, particularly rs7903146, increase T2DM risk. Potential links between genetic variants of the TCF7L2 locus and coronary atherosclerosis are uncertain. We therefore investigated the association between TCF7L2 polymorphisms and angiographically determined CAD in diabetic and non-diabetic patients.
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Germline polymorphisms in genes involved in the CD44 signaling pathway are associated with clinical outcome in localized gastric adenocarcinoma.
Int. J. Cancer
PUBLISHED: 02-11-2011
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The cluster of differentiation 44 (CD44) signaling pathway is crucial in cancer-cell growth, invasion, proliferation and metastasis. CD44 is a transmembrane receptor for hyaluronan and osteopontin, and has recently attracted attention as a gastric cancer stem cell marker. Previous studies showed that polymorphisms in the CD44 gene can influence both human cancer survival and determine cellular response to cytotoxic chemotherapeutics. In addition, CD44 protein overexpression has been associated with poor prognosis in gastric adenocarcinoma (GA). We tested the hypothesis whether polymorphisms involved in the CD44 pathway will predict clinical outcome in patients with localized GA. Either blood or formalin-fixed paraffin-embedded (FFPE) tissues were obtained from 137 patients with localized GA at University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was isolated and polymorphisms within the CD44 pathway were determined by PCR-RFLP technique. In univariate analysis CD44 rs187116 and CD44 rs7116432 were significantly associated with time to tumor recurrence (TTR) and overall survival (OS). After adjusting for covariates, patients harboring at least one G allele of CD44 rs187116 remained significantly associated with TTR (adjusted p=0.009) and OS (adjusted p=0.045). Further, patients harboring CD44 T-A haplotype were at the lowest risk of developing tumor recurrence (HR: 0.255; 95% CI: 0.11-0.591; adjusted p=0.001) and death (HR 0.198; 95% CI: 0.07-0.563; adjusted p=0.002). These results provide the first evidence that CD44 polymorphisms predict clinical outcome in patients with localized GA. This may help to identify localized GA patients at high risk for tumor recurrence.
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Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy.
Ann. Neurol.
PUBLISHED: 02-01-2011
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Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively-acting mutations and recessively-acting loss-of-function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not a disease mechanism for Bethlem myopathy. Our findings have important implications for the genetic evaluation of patients with collagen VI-related myopathies as well as for potential therapeutic interventions for this patient population.
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Survival of metastatic gastric cancer: Significance of age, sex and race/ethnicity.
J Gastrointest Oncol
PUBLISHED: 01-21-2011
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Despite the success of modern chemotherapy in the treatment of large bowel cancers, patients with metastatic gastric cancer continue to have a dismal outcome. Identifying predictive and prognostic markers is an important step to improving current treatment approaches and extending survival.
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Molecular predictors of combination targeted therapies (cetuximab, bevacizumab) in irinotecan-refractory colorectal cancer (BOND-2 study).
Anticancer Res.
PUBLISHED: 11-02-2010
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To test whether intratumoral gene expression levels and germline polymorphisms predict clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab and bevacizumab plus irinotecan (CBI) vs. cetuximab and bevacizumab (CB)(BOND2).
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Germline polymorphisms in genes involved in the IGF1 pathway predict efficacy of cetuximab in wild-type KRAS mCRC patients.
Clin. Cancer Res.
PUBLISHED: 10-08-2010
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The insulin-like growth factor 1 (IGF1) signaling pathway is an important growth-regulatory pathway, which plays a crucial role in colorectal cancer (CRC) proliferation, differentiation, migration, angiogenesis, and apoptosis. Previous studies showed that hyperactivation of the IGF1 receptor (IGF1R) may result in resistance to anti-epidermal growth factor receptor-targeted treatment. We tested whether germline variations within the IGF1 pathway are associated with clinical outcome in wild-type (wt) KRAS drug-refractory metastatic CRC (mCRC) patients who were treated with cetuximab monotherapy (IMC-0144).
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Mucinous adenocarcinomas with intra-abdominal dissemination: a review of current therapy.
Oncologist
PUBLISHED: 07-23-2010
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Peritoneal carcinomatosis has been considered a terminal disease with a median survival time of 5.2-12.6 months. Systemic chemotherapy and cytoreductive surgery (CRS) have long been used to treat macroscopic disease, with limited success. However, a comprehensive treatment approach involving cytroreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) has evolved into a novel approach for peritoneal carcinomatosis. Surgery removes the primary cancer and any dissemination within the peritoneal cavity and adjuvant HIPEC eradicates macroscopic or microscopic tumor residue, thus reducing the risk for recurrence. This approach offers a new potential treatment option for patients with metastatic disease confined to the peritoneum. The present review provides an update of the most recent data on the current therapy for pseudomyxoma peritonei (PMP) and mucinous colorectal adenocarcinoma (MCA) with metastatic disease confined to the peritoneum.
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Optimized allele-specific real-time PCR assays for the detection of common mutations in KRAS and BRAF.
J Mol Diagn
PUBLISHED: 04-29-2010
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Mutations in the oncogenes KRAS and BRAF have been identified as prognostic factors in patients with colorectal diseases and as predictors of negative outcome in epidermal growth factor receptor-targeted therapies. Therefore, accurate mutation detection in both genes, KRAS and BRAF, is of increasing clinical relevance. We aimed at optimizing allele-specific real-time PCR assays for the detection of common mutations in KRAS and the BRAF Val600Glu mutation using allele-specific PCR primers for allelic discrimination and probes (TaqMan) for quantification. Each reaction mix contains a co-amplified internal control to exclude false-negative results. Allele-specific real-time PCR assays were evaluated on plasmid model systems providing a mutation detection limit of 10 copies of mutant DNA in proportions as low as 1% of the total DNA. Furthermore, we analyzed 125 DNA samples prepared from archived, formalin-fixed, paraffin-embedded colorectal carcinomas and compared results with those obtained from direct-sequence analysis. All mutations determined by sequence analysis could be recovered by allele-specific PCR assays. In addition, allele-specific PCR assays clearly identified three additional samples affected by a mutation. We propose these allele-specific real-time PCR assays as a low-cost and fast diagnostic tool for accurate detection of KRAS and BRAF mutations that can be applied to clinical samples.
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Molecular predictive and prognostic markers in colon cancer.
Cancer Treat. Rev.
PUBLISHED: 03-08-2010
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Colorectal cancer remains one of the major cancer related death despite progress in the cytotoxic treatment of colorectal cancer (CRC) over the past decade. The introduction of targeted agents has improved the progression free and overall survival of metastatic disease. However, 40-50% of patients do not experience beneficial effects and it remains a challenge to select patients likely to respond to therapy. Several new molecular predictive and prognostic markers have been identified and are now being translated into routine clinical practice. K-Ras mutation is the first established molecular marker with a lack of response in K-Ras mutated patients treated with an epidermal growth factor receptor (EGFR)-targeted therapy. The validation of predictive and prognostic markers will result in more successful and less toxic therapeutic regimens for cancer patients. This review aims to summarize the most important currently available predictive and prognostic molecular markers in colorectal cancer.
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Vascular endothelial growth factor and epidermal growth factor signaling pathways as therapeutic targets for colorectal cancer.
Gastroenterology
PUBLISHED: 02-04-2010
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Treatment of colorectal cancer (CRC) has developed considerably over the past decade, especially in the areas of targeted therapeutics and biomarker development. Multiple cellular pathways influence the growth and metastatic potential of CRC. Targeted therapies have been designed to interfere with specific molecular events in pathways that mediate tumor growth and progression. Preclinical and clinical studies have shown that the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are valid therapeutic targets for patients with CRC. Monoclonal antibodies and tyrosine kinase inhibitors have been developed to target EGFR, VEGF, and VEGF receptors (VEGFRs) and are important additions to CRC treatment options. We review the most recent data on the VEGF and EGFR signaling pathways and therapeutic reagents designed to target them, provide insights into their mechanisms, and describe results from recent clinical trials.
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Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus.
Ann. Surg.
PUBLISHED: 01-27-2010
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The aim of this study was to determine whether the risk of systemic disease after esophagectomy could be predicted by angiogenesis-related gene polymorphisms.
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Cardiac pathology exceeds skeletal muscle pathology in two cases of limb-girdle muscular dystrophy type 2I.
Muscle Nerve
PUBLISHED: 08-26-2009
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Limb-girdle muscular dystrophy type 2I (LGMD-2I) is caused by mutations in the fukutin-related protein gene (FKRP) that lead to abnormal glycosylation of alpha-dystroglycan in skeletal muscle. Heart involvement in LGMD-2I is common, but little is known about a underlying cardiac pathology. Herein we describe two patients with LGMD-2I (homozygous FKRP mutation c.826C>A, p.Leu276Ile) who developed severe congestive heart failure that required cardiac transplantation. The dystrophic pathology and impairment of alpha-dystroglycan glycosylation were severe in the heart but mild in skeletal muscle, underscoring the lack of correlation between cardiac and skeletal muscle involvement in some LGMD-2I patients.
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Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1).
Hum. Mutat.
PUBLISHED: 06-30-2009
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The ACTA1 gene encodes skeletal muscle alpha-actin, which is the predominant actin isoform in the sarcomeric thin filaments of adult skeletal muscle, and essential, along with myosin, for muscle contraction. ACTA1 disease-causing mutations were first described in 1999, when a total of 15 mutations were known. In this article we describe 177 different disease-causing ACTA1 mutations, including 85 that have not been described before. ACTA1 mutations result in five overlapping congenital myopathies: nemaline myopathy; intranuclear rod myopathy; actin filament aggregate myopathy; congenital fiber type disproportion; and myopathy with core-like areas. Mixtures of these histopathological phenotypes may be seen in a single biopsy from one patient. Irrespective of the histopathology, the disease is frequently clinically severe, with many patients dying within the first year of life. Most mutations are dominant and most patients have de novo mutations not present in the peripheral blood DNA of either parent. Only 10% of mutations are recessive and they are genetic or functional null mutations. To aid molecular diagnosis and establishing genotype-phenotype correlations, we have developed a locus-specific database for ACTA1 variations (http://waimr.uwa.edu.au).
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Different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer.
Oncol. Rep.
PUBLISHED: 04-11-2009
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A glycine to valine substitution at codon 12 (G12V) in Kirsten-Ras (K-Ras) gene has been associated with reduced overall survival in colorectal cancer patients; however, the effect of other K-Ras mutations than G12V still remains unclear. Therefore, we investigated the role of different K-Ras mutations on overall survival in a homogeneous, large patient cohort with standardized therapy and uniform analysis of K-Ras mutation status. The study included 342 patients with histopathologically proven colorectal cancer. Survival data were provided by the federal agency for statistics in Austria. Occurrence of K-Ras mutations at codons 12, 13 and 61 were determined by capillary sequencing. The overall K-Ras mutation frequency in carcinoma tissue was 28%. Carriers of the G12V mutation at the K-Ras gene showed a significantly decreased overall survival compared to carriers of the wild-type [HR=2.56 (1.15-5.69)]. Other mutations than G12V were associated with better overall survival compared to wild-type [HR=0.44 (0.2-0.99)]. In conclusion, for the first time, our study showed clearly that different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer.
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Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.
Prenat. Diagn.
PUBLISHED: 03-07-2009
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Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS.
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Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation.
Neuromuscul. Disord.
PUBLISHED: 03-02-2009
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The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of alpha-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced alpha-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of alpha-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of alpha-dystroglycan hypoglycosylation in skeletal muscle.
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Diagnosis of hepatic iron overload: a family study illustrating pitfalls in diagnosing hemochromatosis.
Diagn. Mol. Pathol.
PUBLISHED: 02-14-2009
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Recent identification of genetic variants in iron storage disease has changed the classification system and diagnostic algorithms for hemochromatosis. Clinical diagnosis of the disease requires phenotypic evidence of iron overload because the commonly disease-associated HFE genotypes have an incomplete penetrance. Furthermore, approximately 20% of patients with a clinical diagnosis of hemochromatosis have no disease-associated genotype, which underlines the importance of clear phenotypic criteria of hemochromatosis. A diagnosis of hemochromatosis cannot be made even in patients with liver cirrhosis simply on the basis of genetic testing that indicates that iron overload is the cause of the disease and not its consequence. Proper diagnosis requires integration of clinical presentation, family history, and the results of biochemical and histopathologic tests. Here we propose a rational diagnostic algorithm for hepatic iron overload syndromes and illustrate potential pitfalls by presenting a family study in a pedigree with rare HFE variants (H63D and E168Q), in cis on the same chromosome. Although the clinical suspicion of hemochromatosis was confirmed by histology, chemical analysis of liver tissue revealed a normal hepatic iron concentration, which is compatible with the genetic finding of 1 normal and 1 doubly mutated allele. In conclusion, clinical suspicion of hemochromatosis and elevated serum iron parameters should prompt HFE genotyping for C282Y and H63D. Should they be uninformative, further genetic tests should be recommended only if iron overload in liver tissue has been confirmed chemically.
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Significant impact of chromosomal locus 1p13.3 on serum LDL cholesterol and on angiographically characterized coronary atherosclerosis.
Atherosclerosis
PUBLISHED: 02-10-2009
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Recently, a significant impact of a new locus on chromosome 1p13.3 on serum LDL (low-density lipoprotein) cholesterol and clinical events of coronary artery disease (CAD) was described. Potential associations between variants on this locus and angiographically characterized coronary atherosclerosis are unknown. We therefore aimed at investigating the association of variants of locus 1p13.3 with coronary atherosclerosis.
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Evaluation of the association of genetic variants on the chromosomal loci 9p21.3, 6q25.1, and 2q36.3 with angiographically characterized coronary artery disease.
Atherosclerosis
PUBLISHED: 01-13-2009
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The chromosomal loci 9p21.3, 6q25.1, and 2q36.3, represented by their respective leading variants rs1333049, rs6922269 and rs2943634, have been linked with a history of coronary artery disease (CAD) by genome-wide association studies. Whereas the association of variant rs1333049 with CAD was analysed in several subsequent studies, replication studies of variants rs6922269 and rs2943634 are missing. Furthermore, no direct association with coronary atherosclerosis has been established. We therefore aimed at investigating the association of the above variants with coronary atherosclerosis.
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Association of a common genetic variant of the IGF-1 gene with event-free survival in patients with HER2-positive breast cancer.
J. Cancer Res. Clin. Oncol.
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Insulin-like growth factor 1 (IGF-1) stimulates mitosis and inhibits apoptosis. High circulating IGF-1 levels are linked with an increased risk of colorectal and breast cancer. Recently, IGF-1 single nucleotide polymorphisms (SNPs), especially variant rs2946834, have been associated with poor clinical outcome in patients with colorectal cancer. In the present study, we aimed to investigate the influence of IGF1 polymorphisms associated with IGF-1 plasma levels on event-free survival in patients with HER2-positive breast cancer.
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Metastatic medulloblastoma in an adolescent with Simpson-Golabi-Behmel syndrome.
Am. J. Med. Genet. A
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We describe the case of a 12-year-old Hispanic male with a clinical and molecular diagnosis of Simpson-Golabi-Behmel Syndrome (SGBS) who subsequently developed metastatic medulloblastoma. While individuals with SGBS have been documented to have increased risk for intra-abdominal tumors such as Wilms tumor and neuroblastoma, medulloblastomas, or CNS tumors in general, have not been reported in patients with this syndrome. Our patient was clinically diagnosed with SGBS as an infant. He presented with many of the common features of the syndrome, such as cleft palate, macroglossia, post-axial polydactyly, "coarse" facial features, and ventricular septal defects (VSDs). Molecular testing performed in April 2009 confirmed the SGBS diagnosis. This testing detected a large intragenic deletion in the GPC3 gene (more than 500 kb, 8 exons) extending from intron 2, 37 kb downstream of exon 2, to the 5 end of the gene, deleting exons 1 and 2. However, subsequent testing by gene-centric high-density array comparative genomic hybridization (aCGH) detected a deletion encompassing only exon 2. Therefore, the exact 5 boundary of the deletion cannot currently be determined, due to an apparent complex rearrangement upstream of exon 1. We present this case of metastatic medulloblastoma as a unique malignancy in a patient with SGBS.
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The functional polymorphism of erythropoietin gene rs1617640 G>T is not associated with susceptibility and clinical outcome of early-stage breast cancer.
Anticancer Res.
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Recent data suggest that erythropoietin (EPO) plays a substantial role in cancer development and clinical outcome by stimulating cell proliferation, invasion and angiogenesis. A functional polymorphism (rs1617640 G>T) in the promoter region of the EPO gene increases EPO protein expression. In the present study, we investigated the association of EPO rs1617640 G>T with susceptibility and clinical outcome of early-stage breast cancer. Genomic DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 controls was genotyped for EPO rs1617640 G>T. No association was found between EPO rs1617640 G>T and early-stage breast cancer susceptibility and clinical outcome (hazard ratio=1.24, 95% confidence interval=1.82-1.90, p=0.31). In conclusion, our findings suggest a lack of influence of EPO rs1617640 G>T on early-stage breast carcinogenesis and clinical outcome.
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Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.
J. Med. Genet.
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Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences.
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Influence of sex on the survival of patients with esophageal cancer.
J. Clin. Oncol.
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The prognostic value of sex for esophageal cancer survival is currently unclear, and growing data suggest that hormonal influences may account for incidence disparities between men and women. Therefore, moving from the hypothesis that hormones could affect the prognosis of patients with esophageal cancer, we investigated the primary hypothesis that sex is associated with survival and the secondary hypotheses that the relationship between sex and survival depends, at least in part, on age, histology, and race/ethnicity.
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ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome.
Nat. Genet.
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Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology.
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Carrier state for the nebulin exon 55 deletion and abnormal prenatal ultrasound findings as potential signs of nemaline myopathy.
Prenat. Diagn.
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To increase awareness to the possibility of nemaline myopathy (NM) when abnormal prenatal ultrasound findings appear together with a carrier state for the common exon 55 deletion in the nebulin gene (NEB) of an Ashkenazi Jewish parent.
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A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients.
BMC Cancer
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The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients.
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DNAJB6 Myopathy: A vacuolar myopathy with childhood onset.
Muscle Nerve
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Introduction: DNAJB6 mutations cause an autosomal dominant myopathy that can manifest as limb-girdle muscular dystrophy (LGMD1D/1E) or distal-predominant myopathy. The majority of patients manifests in adulthood and show vacuolar changes on muscle biopsy. Methods: Clinical, electrophysiological, pathological and molecular findings are reported. Results: We report a 56-year-old woman who, like 3 other family members, became symptomatic in childhood with slowly progressive limb-girdle muscle weakness, normal serum creatine kinase (CK) values, and myopathic electromyographic findings. Her muscle biopsy showed vacuolar changes and congophilic inclusions, and molecular analysis revealed a pathogenic mutation in the DNAJB6 gene. Differences and similarities with previously described cases are discussed. Conclusions: Childhood-onset of DNAJB6-myopathy is more frequent than previously thought; congophilic inclusions can be present in the muscle of these patients. © 2013 Wiley Periodicals, Inc.
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