nave-adult-stem-cells-isolation-from-primary-human-fibroblast-cultures

Na&iuml;ve Adult Stem Cells Isolation from Primary Human Fibroblast Cultures

Over the last decade, several adult stem cell  populations have been identified in human skin 1-4.  The isolation of multipotent adult dermal precursors ...

Technische Universität München

Evidence for extensive locus heterogeneity in Naxos disease.

Preuve de l&#39;h&eacute;t&eacute;rog&eacute;n&eacute;it&eacute; des locus &eacute;tendu dans la maladie de Naxos.

Prove per eterogeneit&agrave; di locus estesa nella malattia di Naxos.

The application of ribozymes for gene therapy of autosomal dominant diseases has become popularized in recent years. Further this technology has widespread utility in the treatment of any disease, acquired or inherited, by inhibition of gene expression. The design of ribozymes is usually accomplished using computer assisted design programs, however they are not very useful in predicting the behavior of the ribozyme in the in vivo setting. To overcome this technical challenge, we developed a simple in vivo strategy to accurately assess the efficiency of ribozyme cleavage that significantly enhances the computer based design programs.

Strategy to assess the efficiency of U1 RNA-hammerhead ribozyme constructs using GFP-tagged targets.

L&#39;application de ribozymes pour la th&eacute;rapie g&eacute;nique des maladies dominantes autosomiques a devenir popularis&eacute;e ces derni&egrave;res ann&eacute;es. De plus, cette technologie a utilitaire g&eacute;n&eacute;ralis&eacute;e dans le traitement de toute maladie, acquis ou h&eacute;rit&eacute;s, par inhibition de l&#39;expression g&eacute;nique. La conception des ribozymes est habituellement accomplie en utilisant des programmes de conception assist&eacute;e par ordinateur, mais ils ne sont pas tr&egrave;s utiles pour pr&eacute;dire le comportement de la ribozyme en milieu in vivo. Pour surmonter ce d&eacute;fi technique, nous avons d&eacute;velopp&eacute; une strat&eacute;gie simple in vivo pour &eacute;valuer avec pr&eacute;cision l&#39;efficacit&eacute; du clivage ribozyme qui am&eacute;liore grandement les programmes de conception sur ordinateur.

Strat&eacute;gie visant &agrave; &eacute;valuer l&#39;efficacit&eacute; des ribozymes U1 RNA-hammerhead construit &agrave; l&#39;aide de cibles GFP-&eacute;tiquet&eacute;e.

L&#39;applicazione di ribozimi per la terapia genica delle malattie autosomiche dominanti ha diventato popolare negli ultimi anni. Ulteriormente questa tecnologia &egrave; diffusa utilit&agrave; nel trattamento di qualsiasi malattia, acquisita o ereditata, di inibizione dell&#39;espressione del gene. Il design dei ribozimi &egrave; compiuto solitamente usando programmi per computer assistita design, tuttavia non sono molto utili nel predire il comportamento del ribozima nell&#39;impostazione in vivo. Per superare questa sfida tecnica, abbiamo sviluppato una semplice strategia in vivo per valutare con precisione l&#39;efficienza del ribozima scissione che migliora significativamente i programmi di disegno computer basata.

Strategia per valutare l&#39;efficienza del ribozima U1 RNA-martello costruisce utilizzando obiettivi GFP-etichettato.

Mutations in the hair keratins hHb1 and hHb6 have been recently reported to cause monilethrix, an autosomal dominant hair shaft disorder, characterized by variable degrees of hair fragility and follicular hyperkeratosis. We found 10 families with monilethrix in whicn the parents were not clinically affected, and sequenced the hair keratin hHb1, hHb2 and hHb6 genes in seven patients. In five patients no mutations were found, while in two patients we identified de novo germline missense mutations at the helix termination motif: E402K (hHb6) and E413K (hHb1).

De novo mutations in monilethrix.

Mutations du cheveux k&eacute;ratine hHb1 et hHb6 ont &eacute;t&eacute; r&eacute;cemment signal&eacute;es provoque le monilethrix, un trouble de l&#39;arbre des cheveux dominante autosomique, caract&eacute;ris&eacute;e par des degr&eacute;s variables de fragilit&eacute; des cheveux et une hyperk&eacute;ratose folliculaire. Nous avons trouv&eacute; 10 familles avec monilethrix whicn les parents n&#39;ont pas &eacute;t&eacute; affect&eacute;s cliniquement et s&eacute;quenc&eacute; les g&egrave;nes cheveux k&eacute;ratine hHb1, hHb2 et hHb6 chez sept patients. Aucune mutation ont &eacute;t&eacute; trouv&eacute;es chez cinq patients, tandis que chez les deux patients, nous avons identifi&eacute; des mutations de novo dans les cellules germinales faux-sens dans le motif de r&eacute;siliation helix : E402K (hHb6) et E413K (hHb1).

Mutations de novo dans le monilethrix.

Mutazioni nei capelli cheratina hHb1 e hHb6 sono stati recentemente segnalate per causare monilethrix, un disturbo di albero capelli autosomica dominante, caratterizzata da gradi variabili di fragilit&agrave; dei capelli e ipercheratosi follicolare. Abbiamo trovato 10 famiglie con monilethrix nel whicn i genitori clinicamente non sono stati influenzati e sequenziato i capelli cheratina hHb1, hHb2 e hHb6 geni in sette pazienti. In cinque pazienti sono stata trovata nessuna mutazione, mentre in due pazienti abbiamo identificato de novo germline mutazioni missenso presso il motivo di cessazione elica: E402K (hHb6) ed E413K (hHb1).

Mutazioni de novo in monilethrix.

Atrichia with papular lesions (APL) (MIM 209 500) is a rare autosomal recessive disease characterized by early onset of atrichia, followed by a papular eruption within the first years of life. Recent studies demonstrating linkage to chromosome 8p21 and further mutation detection in the hairless gene (HR) have established the molecular basis of APL. This study describes the case of a 16-year-old female with APL due to a missense mutation, D1012N, in the hr-thyroid hormone receptor interacting domain 2 (TRID2) of the HR. Using functional and biochemical analysis, it was determined that this mutation does not significantly affect hr-thyroid hormone receptor interaction. This result suggests that the TRID2 domain either is dispensable in the hr-TR interaction or is not involved in the pathogenesis of APL.

Interaction of hairless and thyroid hormone receptor is not involved in the pathogenesis of atrichia with papular lesions.

Atrichie avec l&eacute;sions papulaires (APL) (MIM 209 500) est une maladie autosomique r&eacute;cessive rare, caract&eacute;ris&eacute;e par l&#39;apparition pr&eacute;coce d&#39;Atrichie, suivie d&#39;une &eacute;ruption papuleuse dans les premi&egrave;res ann&eacute;es de la vie. R&eacute;centes &eacute;tudes mettant en &eacute;vidence le lien avec chromosome 8p 21 et plus la d&eacute;tection de mutations dans le g&egrave;ne nu (HR) ont &eacute;tabli les bases mol&eacute;culaires de l&#39;APL. Cette &eacute;tude d&eacute;crit le cas d&#39;une adolescente de 16 ans avec APL due &agrave; une mutation faux-sens, D1012N, dans le domaine de l&#39;interaction r&eacute;cepteur du hr-thyro&iuml;de hormone 2 (TRID2) de la HR. &agrave; l&#39;aide d&#39;analyses biochimiques et fonctionnelles, il a &eacute;t&eacute; d&eacute;termin&eacute; que cette mutation n&#39;affecte pas significativement interaction r&eacute;cepteur hormone thyro&iuml;dienne-hr. Ce r&eacute;sultat sugg&egrave;re que le domaine TRID2 est dispensable dans l&#39;interaction RH-TR ou n&#39;est pas impliqu&eacute; dans la pathog&eacute;nie de l&#39;APL.

Interaction de r&eacute;cepteur hormonal sans poil et de la thyro&iuml;de n&#39;est pas impliqu&eacute;e dans la pathog&eacute;nie d&#39;Atrichie avec l&eacute;sions papulaires.

Atrichia con lesioni papulose (APL) (MIM 209 500) &egrave; una rara malattia autosomica recessiva caratterizzata da esordio precoce di atrichia, seguita da un&#39;eruzione papulose entro i primi anni di vita. Recenti studi di linkage dimostrando al cromosoma 8p 21 e ulteriore rilevazione di mutazione del gene hairless (HR) hanno stabilito le basi molecolari di APL. Questo studio descrive il caso di una femmina di 16 anni con APL a causa di una mutazione missenso, D1012N, nel dominio interagenti di recettore degli ormoni tiroidei hr 2 (TRID2) di HR mediante analisi biochimica e funzionale, &egrave; stato stabilito che questa mutazione non influisce in maniera significativa interazione del recettore dell&#39;ormone tiroideo-hr. Questo risultato suggerisce che il dominio TRID2 &egrave; superfluo nell&#39;interazione hr-TR o non &egrave; coinvolto nella patogenesi dell&#39;APL.

Interazione del recettore dell&#39;ormone della tiroide e senza peli non &egrave; coinvolto nella patogenesi dell&#39;atrichia con lesioni papulose.

Hair follicle cycling is a highly regulated and dynamic cellular process consisting of phases of growth, regression, and quiescence. The hairless (hr) gene encodes a nuclear factor that is highly expressed in the skin, where it appears to be an essential regulator during the regression in the catagen hair follicle. In hairless mice, as well as humans with congenital atrichia, the absence of hr protein initiates a premature and abnormal catagen due to defects in the signaling required for hair follicle remodeling. Here, we report that hr protein is a nuclear protein that is tightly associated with the nuclear matrix scaffold. Using a series of deletion constructs of the mouse hr gene, we monitored the sub-cellular localization of the recombinant protein by in situ immunolocalization and biochemical fractionation after nuclear matrix extraction of transiently transfected cells. We identified a novel nuclear matrix-targeting signal (NMTS) in the hr protein and mapped the domain to amino acid residues 111-186 of the mouse hr sequence. Furthermore, we provide evidence that this region not only mediates the interaction of hr with components of the nuclear architecture, but also specifies the sub-nuclear location of the hr protein to nuclear domains containing deacetylase activity. The N-terminal region directs hr to a speckled nuclear pattern that co-localizes with the histone deacetylase 3 (HDAC), but not with HDAC1 or HDAC7. Based on our findings, we propose that hr protein is part of a specific multi-protein repressor complex and that hr may be involved in chromatin remodeling.

Hairless contains a novel nuclear matrix targeting signal and associates with histone deacetylase 3 in nuclear speckles.

Follicule pileux le cyclisme est un processus cellulaire tr&egrave;s r&eacute;glement&eacute; et dynamique compos&eacute;e des phases de croissance, de r&eacute;gression et de quiescence. Le g&egrave;ne nu (hr) code pour un facteur nucl&eacute;aire qui est fortement exprim&eacute; dans la peau, o&ugrave; il semble &ecirc;tre un r&eacute;gulateur essentiel durant la r&eacute;gression dans le follicule pileux catag&egrave;ne. Dans la souris sans poils, comme les humains avec atrichia cong&eacute;nitale, l&#39;absence de la prot&eacute;ine RH lance un catag&egrave;ne pr&eacute;matur&eacute;e et anormale due &agrave; des d&eacute;fauts dans la signalisation n&eacute;cessaire pour transformer de la follicule de cheveux. Nous rapportons ici, que la prot&eacute;ine RH est une prot&eacute;ine nucl&eacute;aire qui est &eacute;troitement li&eacute;e &agrave; l&#39;&eacute;chafaud de la matrice nucl&eacute;aire. &Agrave; l&#39;aide d&#39;une s&eacute;rie de constructions de d&eacute;l&eacute;tion du g&egrave;ne RH souris, nous avons suivi la localisation subcellulaire de la prot&eacute;ine recombinante par immunolocalisation in situe et de fractionnement biochimique apr&egrave;s extraction de la matrice nucl&eacute;aire des cellules transfect&eacute;es transitoirement. Nous avons identifi&eacute; un roman nucl&eacute;aire ciblage matrice signal (territoires non m&eacute;tropolitains) dans la prot&eacute;ine RH et mapp&eacute; le domaine &agrave; acide amin&eacute; r&eacute;sidus 111-186 de la s&eacute;quence de RH de souris. En outre, nous fournissons des preuves que cette r&eacute;gion non seulement intervient dans l&#39;interaction des ressources humaines avec des composants de l&#39;architecture nucl&eacute;aire, mais sp&eacute;cifie &eacute;galement la localisation sub-nucl&eacute;aire de la prot&eacute;ine RH vers des domaines nucl&eacute;aires contenant l&#39;activit&eacute; d&eacute;sac&eacute;tylase. La r&eacute;gion N-terminale redirige RH &agrave; une mouchet&eacute; nucl&eacute;aire qui co-localise avec l&#39;histone d&eacute;sac&eacute;tylase (HDAC) de 3, mais pas avec HDAC1 ou HDAC7. D&#39;apr&egrave;s nos constatations, nous proposons que la prot&eacute;ine RH fait partie d&#39;un r&eacute;presseur multi-prot&eacute;ine sp&eacute;cifique et complex et que RH peut-&ecirc;tre &ecirc;tre impliqu&eacute; dans le remodelage de la chromatine.

Epil&eacute;es contient une nouvelle matrice nucl&eacute;aire ciblant le signal et associe &agrave; histone deacetylase 3 en granulations nucl&eacute;aires.

Follicolo pilifero in bicicletta &egrave; un processo cellulare altamente regolamentato e dinamico, costituito da fasi di crescita, di regressione e di quiescenza. Il gene hairless (hr) codifica per un fattore nucleare che &egrave; altamente espresso nella pelle, dove sembra di essere un regolatore essenziale durante la regressione nel follicolo dei capelli catagen. Nei topi glabri, cos&igrave; come gli esseri umani con atrichia congenita, l&#39;assenza della proteina hr avvia un catagen prematura e anormale a causa di difetti nella segnalazione richiesto per rimodellamento del follicolo pilifero. Qui, segnaliamo che hr proteina &egrave; una proteina nucleare che &egrave; strettamente associata con l&#39;impalcatura della matrice nucleare. Utilizzando una serie di costrutti di delezione del gene del mouse hr, abbiamo monitorato la localizzazione subcellulare delle proteine ricombinanti da immunolocalization in situ e biochimica frazionamento dopo l&#39;estrazione della matrice nucleare delle cellule transitoriamente transfected. Abbiamo identificato un romanzo nucleare matrice di targeting signal (NMTS) della proteina hr e mappato il dominio dell&#39;amminoacido residui 111-186 della sequenza hr del mouse. Inoltre, forniamo prove che questa regione non solo da intermediario l&#39;interazione di hr con componenti dell&#39;architettura nucleare, ma anche di specificare il percorso subnucleare della proteina nucleare domini contenenti attivit&agrave; di deacetylase hr. La regione N-terminale dirige hr ad un pattern speckled nucleare che co-localizes con il deacetylase dell&#39;istone 3 (HDAC), ma non con HDAC1 o HDAC7. Basato sui nostri risultati, proponiamo che hr proteina fa parte di un repressore specifico multi-protein complesso e che ora possa essere coinvolti nel rimodellamento della cromatina.

Glabro contiene una romanzo matrice nucleare segnale di targeting e associa deacetylase dell&#39;istone 3 in macchioline nucleare.

Sindrome di progeria di Hutchinson-Gilford (HGPS, OMIM 176670) &egrave; una rara malattia sporadica con un&#39;incidenza di circa 1 per 8 milioni di nati vivi. L&#39;aspetto fenotipico &egrave; costituito da bassa statura, naso scolpito, alopecia, vene prominenti del cuoio capelluto, viso piccolo, perdita di grasso sottocutaneo, cianosi mid-facial debole e unghie distrofiche. HGPS &egrave; causata da mutazioni in LMNA, il gene che codifica lamins nucleari A e C. La mutazione pi&ugrave; comune in soggetti con HGPS &egrave; una sostituzione di coppia singolo-base de novo, G608G (GGC &amp;gt; GGT), nell&#39;esone 11 di LMNA. Questo crea un sito di donatore di splicing anormale, che porta all&#39;espressione di una proteina tronca.

Fibroblasti dermici nella sindrome di progeria di Hutchinson-Gilford con la mutazione G608G A lamina dismorfico nuclei e sono ipersensibili a stress da calore.

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare sporadic disorder with an incidence of approximately 1 per 8 million live births. The phenotypic appearance consists of short stature, sculptured nose, alopecia, prominent scalp veins, small face, loss of subcutaneous fat, faint mid-facial cyanosis, and dystrophic nails. HGPS is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. The most common mutation in subjects with HGPS is a de novo single-base pair substitution, G608G (GGC>GGT), within exon 11 of LMNA. This creates an abnormal splice donor site, leading to expression of a truncated protein.

Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress.

Syndrome de progeria de Hutchinson-Gilford (hormones de croissance, OMIM 176670) est une maladie sporadique rare dont l&#39;incidence est d&#39;environ 1 pour 8 millions de naissances vivantes. L&#39;apparence ph&eacute;notypique se compose d&#39;insuffisance staturale, nez sculpt&eacute;, alop&eacute;cie, veines du cuir chevelu pro&eacute;minent, petit visage, perte de graisse sous-cutan&eacute;e, l&eacute;g&egrave;re cyanose mid-facial et ongles dystrophiques. Hormones de croissance est due &agrave; des mutations dans le g&egrave;ne LMNA, le g&egrave;ne qui code nucl&eacute;aires lamines A et C. La mutation la plus courante chez les sujets atteints d&#39;hormones de croissance est une substitution de base unique paire de novo, G608G (GGC &gt; GGT), au sein de l&#39;exon 11 du g&egrave;ne LMNA. Cela cr&eacute;e un site donneur d&#39;&eacute;pissage anormal, conduisant &agrave; l&#39;expression d&#39;une prot&eacute;ine tronqu&eacute;e.

Des fibroblastes dermiques dans le syndrome de Hutchinson-Gilford progeria avec la mutation A G608G lagoutte ont des noyaux dysmorphiques et pr&eacute;sentent une hypersensibilit&eacute; au stress thermique.

Hutchinson-Gilford progeria syndrome (HGPS; Online Mendelian Inheritance in Man accession no. 176670) is a rare disorder that is characterized by segmental premature aging and death between 7 and 20 years of age from severe premature atherosclerosis. Mutations in the LMNA gene are responsible for this syndrome. Approximately 80% of HGPS cases are caused by a G608 (GGC-->GGT) mutation within exon 11 of LMNA, which elicits a deletion of 50 aa near the C terminus of prelamin A. In this article, we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-dependent manner. In human HGPS fibroblast cultures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformations and invaginations preventable by farnesyltransferase inhibition. Nuclear alterations affect cell-cycle progression and cell migration and elicit premature senescence. Strikingly, skin biopsy sections from a subject with HGPS showed that the truncated lamin A accumulates primarily in the nuclei of vascular cells. This finding suggests that accumulation of progerin is directly involved in vascular disease in progeria.

Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody.

Syndrome de Hutchinson-Gilford progeria (hormones de croissance ; H&eacute;r&eacute;dit&eacute; mend&eacute;lienne en ligne dans l&#39;adh&eacute;sion de l&#39;homme n&deg; 176670) est une maladie rare qui se caract&eacute;rise par un vieillissement pr&eacute;matur&eacute; segmentaire et mort entre 7 et 20 ans de grave ath&eacute;roscl&eacute;rose pr&eacute;matur&eacute;e. Des mutations du g&egrave;ne LMNA sont responsables de ce syndrome. Environ 80 % des cas des hormones de croissance sont caus&eacute;es par un G608 mutation du g&egrave;ne LMNA, qui suscite une d&eacute;l&eacute;tion de 50 (GGC--&gt; GGT) exon 11 aa pr&egrave;s du terminal C de l&#39;identification du prelamin A. Dans cet article, nous pr&eacute;sentons des preuves que le mutant lamin un (progerin) s&#39;accumule dans le noyau d&#39;une mani&egrave;re d&eacute;pendante de l&#39;&acirc;ge cellulaire. Dans les cultures de fibroblastes des hormones de croissance humaines, nous avons observ&eacute;, en m&ecirc;me temps &agrave; accumulation progerin nucl&eacute;aire, des d&eacute;formations s&eacute;v&egrave;res enveloppe nucl&eacute;aire et des invaginations &eacute;vitables par inhibition de la farnesyltransferase. Les alt&eacute;rations nucl&eacute;aires affectent le cycle cellulaire la progression et la migration cellulaire et d&eacute;clencher la s&eacute;nescence pr&eacute;matur&eacute;e. &Eacute;tonnamment, coupes de biopsie de peau d&#39;un sujet avec des hormones de croissance qui a montr&eacute; la lamin tronqu&eacute; Qu&#39;a s&#39;accumule principalement dans les noyaux des cellules vasculaires. Cette constatation donne &agrave; penser que l&#39;accumulation de progerin est directement impliqu&eacute;e dans la maladie vasculaire dans la progeria.

Mutant de progeria de Hutchinson-Gilford lamin A principalement cible les cellules vasculaires humaines tel que d&eacute;tect&eacute; par un anticorps G608G A anti-Lamin.

Sindrome di Hutchinson-Gilford progeria (HGPS; Online Mendelian Inheritance in adesione Man n. 176670) &egrave; una malattia rara caratterizzata da invecchiamento prematuro segmentale e morte tra i 7 e i 20 anni da grave arteriosclerosi prematura. Le mutazioni del gene LMNA sono responsabili di questa sindrome. Circa l&#39;80% dei casi HGPS sono causati da un G608 mutazione (GGC--&gt; GGT) nell&#39;esone 11 di LMNA, che suscita una delezione di 50 aa vicino capolinea di prelamin A. C In questo articolo, vi presentiamo la prova che il mutante lamina A (progerin) si accumula nel nucleo in maniera et&agrave;-dipendente dal cellulare. Nelle culture umane del fibroblasto HGPS, osservammo, simultaneamente per accumulo di progerin nucleare, busta nucleare gravi deformazioni e invaginations prevenibile tramite inibizione di farnesyltransferase. Alterazioni nucleari possono influenzare il ciclo cellulare delle cellule e progressione migrazione e suscitano senescenza precoce. Sorprendentemente, sezioni di biopsia della pelle da un soggetto con HGPS che ha mostrato l&#39;Abi troncato A si accumula principalmente nei nuclei delle cellule vascolari. Questa scoperta suggerisce che accumulo di progerin &egrave; direttamente coinvolto nella malattia vascolare in progeria.

Mutante di progeria di Hutchinson-Gilford lamin A principalmente gli obiettivi umane cellule vascolari come rilevato da un anticorpo anti-Lamin A G608G.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C --> T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed "progerin/LADelta50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LADelta50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LADelta50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LADelta50. Furthermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleated, implicating progerin/LADelta50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.

A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.

Syndrome de progeria de Hutchinson-Gilford (hormones de croissance) est une maladie g&eacute;n&eacute;tique rare caract&eacute;ris&eacute;e par un vieillissement pr&eacute;matur&eacute; dramatique. Hormones de croissance classique est caus&eacute;e par une mutation de novo point dans l&#39;exon 11 (r&eacute;sidu 1824, C--&gt; T) du g&egrave;ne LMNA, activant un donneur d&#39;&eacute;pissage cryptiques et r&eacute;sultant en un mutant lamin prot&eacute;ine A (LA) appel&eacute; &laquo; progerin/LADelta50 &raquo; qui n&#39;a pas le site de clivage normal pour supprimer un groupe de farn&eacute;syl C-terminal. Au cours de l&#39;interphase, irr&eacute;versiblement FARN&Eacute;SYL&Eacute;E progerin/LADelta50 d&#39;ancrer &agrave; la membrane nucl&eacute;aire et provoque blebbing nucl&eacute;aire caract&eacute;ristique. Localisation de Progerin/LADelta50 et le comportement au cours de la mitose, cependant, sont totalement inconnus. Nous rapportons ici que progerin/LADelta50 mislocalizes en agr&eacute;gats cytoplasmiques insolubles et des membranes au cours de la mitose et provoque la binucl&eacute;ation et la s&eacute;gr&eacute;gation des chromosomes anormaux. Ces ph&eacute;notypes sont sauv&eacute;s en grande partie avec des inhibiteurs de farnesyltransferase ou un mutant farnesylation-incomp&eacute;tents progerin/LADelta50. En outre, nous d&eacute;montrons que de petites quantit&eacute;s de progerin/LADelta50 existent dans les fibroblastes normaux, et un pourcentage significatif de ces progerin/LADelta50-exprimant les cellules normales sont binucl&eacute;&eacute;es, impliquant des progerin/LADelta50 comme provoquant des d&eacute;fauts mitotiques similaires dans le processus normal de vieillissement. Nos r&eacute;sultats pr&eacute;sentent une preuve d&#39;anomalies mitotiques en hormones de croissance et peut faire la lumi&egrave;re sur le ph&eacute;nom&egrave;ne g&eacute;n&eacute;ral du vieillissement.

Un lamin une isoforme de la prot&eacute;ine surexprim&eacute;e dans le syndrome de Hutchinson-Gilford progeria interf&egrave;re avec la mitose dans les cellules normales et de progeria.

Sindrome di Hutchinson-Gilford progeria (HGPS) &egrave; una malattia genetica rara caratterizzata da invecchiamento prematuro drammatica. HGPS classica &egrave; causata da una mutazione de novo punto nell&#39;esone 11 (residuo del 1824, C--&gt; T) del gene LMNA, attivando un criptico splice donatore e risultante in un mutante lamina proteina A (LA) chiamata &quot;progerin/LADelta50&quot; che manca il sito di clivaggio normale per rimuovere un gruppo di farnesil C-terminale. Durante l&#39;interfase, irreversibilmente farnesylated progerin/LADelta50 ancore alla membrana nucleare e provoca la caratteristica nucleare blebbing. Localizzazione Progerin/LADelta50 e il comportamento durante la mitosi, tuttavia, sono completamente sconosciuti. Qui, segnaliamo che progerin/LADelta50 mislocalizes in aggregati citoplasmatici insolubili e membrane durante la mitosi e le cause binucleation e segregazione del cromosoma anormale. Questi fenotipi sono in gran parte salvati con inibitori di farnesyltransferase o un mutante incompetente farnesylation progerin/LADelta50. Inoltre, ci dimostrano che piccole quantit&agrave; di progerin/LADelta50 esiste in fibroblasti normali, e una percentuale significativa di questi progerin/LADelta50-esprimendo le cellule normali sono binucleate, implicando progerin/LADelta50 come causando difetti simili mitotici nel normale processo di invecchiamento. I nostri risultati presentano prove di anormalit&agrave; mitotica in HGPS e pu&ograve; far luce sul fenomeno generale dell&#39;invecchiamento.

Una lamina un&#39;isoforma proteica overexpressed in sindrome di progeria di Hutchinson-Gilford interferisce con la mitosi in cellule normali e progeria.

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.

Syndrome de progeria de Hutchinson-Gilford (hormones de croissance, OMIM 176670) est une affection rare caract&eacute;ris&eacute;e par vieillissement acc&eacute;l&eacute;r&eacute; et une mort pr&eacute;coce, souvent de maladie accident vasculaire c&eacute;r&eacute;bral ou de l&#39;art&egrave;re coronaire. 90 % des cas des hormones de croissance portent le g&egrave;ne LMNA G608G (GGC &gt; GGT) mutation au sein de l&#39;exon 11 du g&egrave;ne LMNA, activant un site donneur d&#39;&eacute;pissage qui se traduit par la production d&#39;une forme n&eacute;gative dominante de lamin une prot&eacute;ine, not&eacute;e progerin. D&eacute;pistage 150 biopsies de la peau des individus non affect&eacute;s (nouveau-n&eacute; &agrave; 97 ans) ont montr&eacute; qu&#39;un &eacute;v&eacute;nement semblable d&#39;&eacute;pissage se produit in vivo, &agrave; un bas niveau de la peau &agrave; tout &acirc;ge. Alors que progerin mRNA demeure faible, que la prot&eacute;ine s&#39;accumule dans la peau avec l&#39;&acirc;ge dans un sous-ensemble des fibroblastes dermiques et quelques-uns en phase terminale diff&eacute;renci&eacute;es des k&eacute;ratinocytes. Progerin-positif fibroblastes localiser pr&egrave;s de la membrane basale et dans le derme papillaire de la peau adulte jeune ; Toutefois, leur nombre augmente et leur r&eacute;partition atteint le derme r&eacute;ticulaire profond dans la peau de personnes &acirc;g&eacute;e. Nos r&eacute;sultats d&eacute;montrent que les progerin expression est un biomarqueur du vieillissement cellulaire normal et peut-&ecirc;tre potentiellement &ecirc;tre li&eacute;e &agrave; la diff&eacute;renciation terminale et s&eacute;nescence chez les personnes &acirc;g&eacute;es.

La forme mutante de Lagana A qui provoque la progeria de Hutchinson-Gilford est un biomarqueur du vieillissement cellulaire dans la peau humaine.

Sindrome di progeria di Hutchinson-Gilford (HGPS, OMIM 176670) &egrave; una malattia rara caratterizzata da invecchiamento e morte precoce, spesso da ictus o malattia coronarica. il 90% dei casi HGPS portano il G608G LMNA (GGC &amp;gt; GGT) mutazione nell&#39;esone 11 di LMNA, attivando un sito di splice donatore che si traduce nella produzione di una forma dominante negativa di lamina una proteina, denotato progerin. Screening 150 biopsie cutanee da individui inalterati (neonati di 97 anni) ha mostrato che un simile evento splicing si verifica in vivo ad un livello basso in pelle a tutte le et&agrave;. Mentre progerin mRNA rimane basse, che la proteina si accumula nella pelle con l&#39;et&agrave; in un sottoinsieme dei fibroblasti dermici e in pochi terminalmente differenziano dei cheratinociti. Progerin-positivi fibroblasti localizzare vicino la membrana basale e nel derma papilla della pelle giovane adulto; Tuttavia, aumentare i numeri e la loro distribuzione raggiunge il derma reticolare profondo nella pelle anziana. I nostri risultati dimostrano che progerin espressione &egrave; un biomarker di invecchiamento cellulare normale e potenzialmente pu&ograve; essere legata alla differenziazione terminale e senescenza in individui anziani.

La forma mutante di una lamina che causa la progeria di Hutchinson-Gilford &egrave; un biomarker di invecchiamento cellulare nella pelle umana.

The characteristic alopecia associated with mutations in the hairless (hr) and vitamin D receptor (VDR) genes defines the resulting genetic disorders, known as atrichia and VDRRIIa rickets, as phenocopies. In both cases, the separation of the dermal papilla from the regressing hair follicle at the onset of the first catagen phase of the hair cycle and the development of dermal cysts and utricules subsequent to mutation of either gene suggests that their activities affect the same regulatory pathways. VDR functions as a hormonally activated transcription factor, and a role in transcription has been postulated for Hr due in part to its nuclear localization and homology with the GATA-1 zinc-finger domain. Therefore, we examined the hypothesis that VDR and Hr have a direct regulatory effect on each other via a transcriptional mechanism. Ectopic expression of the VDR repressed hr promoter activity in HaCaT cells and primary human keratinocytes (PHKs). While this repression occurs in the absence of 1,25 dihydroxyvitamin D3 (D3), the addition of ligand greatly augments the effect. However, we also demonstrate the rare phenomenon of ligand-independent promoter transactivation by VDR. We show that the full-length promoter is transactivated by VDR in a ligand-independent and cell type-specific manner, suggesting that direct transcriptional regulation of hr by the VDR accounts in part for the phenotypic overlap between atrichia and VDRRIIa rickets.

Ligand-independent regulation of the hairless promoter by vitamin D receptor.

L&#39;alop&eacute;cie caract&eacute;ristique associ&eacute;e &agrave; des mutations dans le glabre (RH) et les g&egrave;nes de r&eacute;cepteurs (VDR) de vitamine D d&eacute;finit les r&eacute;sultantes des troubles g&eacute;n&eacute;tiques, appel&eacute;es atrichia et rachitisme VDRRIIa, comme ph&eacute;nocopies. Dans les deux cas, la s&eacute;paration de la papille dermique du follicule de cheveux r&eacute;gression au d&eacute;but de la premi&egrave;re phase catag&egrave;ne du cycle pilaire et le d&eacute;veloppement de kystes par voie cutan&eacute;e et utricules &agrave; la suite de la mutation de deux g&egrave;nes sugg&egrave;re que leurs activit&eacute;s influent sur les m&ecirc;mes voies r&eacute;glementaires. Fonctions VDR comme un facteur de transcription hormonalement activ&eacute;s et un r&ocirc;le dans la transcription a &eacute;t&eacute; postul&eacute; pour Hr due en partie &agrave; sa localisation nucl&eacute;aire et l&#39;homologie avec le domaine de doigt de zinc GATA-1. Par cons&eacute;quent, nous avons examin&eacute; l&#39;hypoth&egrave;se que les VDR et RH ont un effet r&eacute;gulateur direct les uns des autres par un m&eacute;canisme de transcription. L&#39;expression ectopique de la VDR r&eacute;prim&eacute;e RH activit&eacute; de promoteur dans les cellules HaCaT et des k&eacute;ratinocytes humains primaires (PHKs). Alors que cette r&eacute;pression se produit en l&#39;absence de 1,25 dihydroxyvitamine D3 (D3), l&#39;ajout du ligand augmente consid&eacute;rablement l&#39;effet. Cependant, nous d&eacute;montrons &eacute;galement le ph&eacute;nom&egrave;ne rare de transactivation de promoteur ind&eacute;pendant du ligand par VDR. Nous montrons que le promoteur pleine longueur est transactivated par VDR dans une ind&eacute;pendante du ligand et de mani&egrave;re sp&eacute;cifique au type de cellule, sugg&eacute;rant cette r&eacute;gulation transcriptionnelle directe des ressources humaines par les comptes VDR en partie pour le chevauchement ph&eacute;notypique entre atrichia et rachitisme VDRRIIa.

R&egrave;glement ind&eacute;pendant du ligand du promoteur glabre de r&eacute;cepteur de la vitamine D.

Il caratteristico alopecia associata a mutazioni nel glabri (hr) e vitamina D geni del recettore (VDR) definisce i disturbi genetici risultanti, conosciuti come atrichia e rachitismo VDRRIIa, come fenocopie. In entrambi i casi, la separazione tra la papilla dermica dal follicolo pilifero regressione all&#39;esordio della prima fase catagen del ciclo del capello e lo sviluppo di cisti cutanee e utricules dopo la mutazione del gene o suggerisce che le loro attivit&agrave; possono influenzare i percorsi normativi stessi. Funzioni VDR come un fattore di trascrizione ormonalmente attivo e un ruolo nella trascrizione &egrave; stata postulata per Hr dovuta in parte alla sua localizzazione nucleare e omologia con il dominio zinc-finger GATA-1. Pertanto, abbiamo esaminato l&#39;ipotesi che VDR e risorse umane hanno un effetto normativo diretto a vicenda attraverso un meccanismo trascrizionale. Espressione ectopica di VDR represso attivit&agrave; promotore hr in cellule HaCaT e cheratinociti umani primari (PHKs). Mentre questa repressione si verifica in assenza di 1,25 diidrossivitamina D3 (D3), l&#39;aggiunta di ligand potenzia notevolmente l&#39;effetto. Tuttavia, abbiamo anche dimostrare il raro fenomeno di transattivazione ligando-indipendente promotore di VDR. Dimostriamo che il promotore full-length &egrave; transactivated da VDR in un ligando-indipendente e in modo specifico del tipo di cellula, suggerendo quello diretto regolamento transcriptional di hr dai conti di VDR in parte per la sovrapposizione fenotipica tra atrichia e VDRRIIa rachitismo.

Ligando-indipendente regolazione del promotore glabro di vitamin D receptor.

Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by point mutation in LMNA encoding A-type nuclear lamins. The mutations in LMNA activate a cryptic splice donor site, resulting in expression of a truncated, prenylated prelamin A called progerin. Expression of progerin leads to alterations in nuclear morphology, which may underlie pathology in HGPS. We generated transgenic mice expressing progerin in epidermis under control of a keratin 14 promoter. The mice had severe abnormalities in morphology of skin keratinocyte nuclei, including nuclear envelope lobulation and decreased nuclear circularity not present in transgenic mice expressing wild-type human lamin A. Primary keratinocytes isolated from these mice had a higher frequency of nuclei with abnormal shape compared to those from transgenic mice expressing wild-type human lamin A. Treatment with a farnesyltransferase inhibitor significantly improved nuclear shape abnormalities and induced the formation of intranuclear foci in the primary keratinocytes expressing progerin. Similarly, spontaneous immortalization of progerin-expressing cultured keratinocytes selected for cells with normal nuclear morphology. Despite morphological alterations in keratinocyte nuclei, mice expressing progerin in epidermis had normal hair grown and wound healing. Hair and skin thickness were normal even after crossing to Lmna null mice to reduce or eliminate expression of normal A-type lamins. Although progerin induces significant alterations in keratinocyte nuclear morphology that are reversed by inhibition of farnesyltransferasae, epidermal expression does not lead to alopecia or other skin abnormalities typically seen in human subjects with HGPS.

Epidermal expression of the truncated prelamin A causing Hutchinson-Gilford progeria syndrome: effects on keratinocytes, hair and skin.

Syndrome de progeria de Hutchinson-Gilford (hormones de croissance) est un trouble de vieillissement acc&eacute;l&eacute;r&eacute;, caus&eacute; par une mutation ponctuelle dans le g&egrave;ne LMNA encodage de type lamines nucl&eacute;aires. Les mutations dans le g&egrave;ne LMNA activent un site donneur d&#39;&eacute;pissage cryptique, ayant pour r&eacute;sultat l&#39;expression d&#39;une identification du prelamin pr&eacute;nyl&eacute;s tronqu&eacute;, un progerin appel&eacute;. Expression de progerin entra&icirc;ne des modifications dans la morphologie nucl&eacute;aire, ce qui pourrait expliquer la pathologie en hormones de croissance. Nous avons g&eacute;n&eacute;r&eacute; des souris transg&eacute;niques exprimant progerin dans &eacute;piderme sous contr&ocirc;le d&#39;un promoteur 14 de k&eacute;ratine. Les souris avaient des anomalies graves dans la morphologie des noyaux de k&eacute;ratinocytes de peau, y compris lobulation enveloppe nucl&eacute;aire et une diminution circularit&eacute; nucl&eacute;aire absente chez les souris transg&eacute;niques exprimant sauvage humaine Lagana A. Primary k&eacute;ratinocytes isol&eacute;s de ces souris avaient une fr&eacute;quence plus &eacute;lev&eacute;e des noyaux avec forme anormale par rapport &agrave; ceux des souris transg&eacute;niques exprimant sauvage humaine Lagana A. traitement avec un inhibiteur de la farnesyltransferase significativement am&eacute;lior&eacute; des anomalies de forme nucl&eacute;aire et induit la formation de foyers intranucl&eacute;aires dans les k&eacute;ratinocytes primaires exprimant progerin. De m&ecirc;me, spontan&eacute;e immortalisation des k&eacute;ratinocytes cultiv&eacute;es exprimant progerin, s&eacute;lectionn&eacute;s pour les cellules avec une morphologie nucl&eacute;aire normale. Malgr&eacute; les alt&eacute;rations morphologiques dans les noyaux des k&eacute;ratinocytes, des souris exprimant progerin dans l&#39;&eacute;piderme avaient cheveux normaux cultiv&eacute;s et la cicatrisation. &Eacute;paisseur de la peau et les cheveux &eacute;taient normaux, m&ecirc;me apr&egrave;s le passage &agrave; des souris nulle Lmna pour r&eacute;duire ou &eacute;liminer l&#39;expression des lamines de type normales. Bien que progerin induit des modifications importantes dans la morphologie nucl&eacute;aire k&eacute;ratinocytes qui sont renvers&eacute;es par l&#39;inhibition de la farnesyltransferasae, expression &eacute;pidermique ne conduit pas &agrave; l&#39;alop&eacute;cie ou d&#39;autres anomalies de la peau g&eacute;n&eacute;ralement vus dans les sujets humains avec des hormones de croissance.

Expression &eacute;pidermique de l&#39;identification du prelamin tronqu&eacute; un syndrome de progeria de Hutchinson-Gilford causant : effets sur la peau, des cheveux et des k&eacute;ratinocytes.

Sindrome di Hutchinson-Gilford progeria (HGPS) &egrave; un disordine di invecchiamento accelerato causato dalla mutazione puntiforme in LMNA codifica di tipo lamins nucleari. Le mutazioni in LMNA attivano un sito donatore splice criptico, con conseguente espressione di un prenylated di prelamin troncato, un progerin chiamato. Espressione di progerin conduce ad alterazioni nella morfologia nucleare, che pu&ograve; essere alla base di patologia in HGPS. Abbiamo generato topi transgenici che esprimono progerin nell&#39;epidermide sotto il controllo di un promotore di cheratina 14. I topi avevano gravi anomalie nella morfologia dei nuclei di cheratinociti della pelle, tra cui busta nucleare lobatura e diminuito circolarit&agrave; nucleare non presente nei topi transgenici che esprimono la wild-type umano DALI A. Primary keratinocytes isolato da questi topi aveva una frequenza pi&ugrave; alta dei nuclei con forma anomala rispetto a quelle da topi transgenici che esprimono la wild-type umano DALI A. trattamento con un inibitore di farnesyltransferase significativamente migliorato anomalie di forma nucleari e induce la formazione di foci intranucleari nei cheratinociti primari esprimendo progerin. Allo stesso modo, spontaneo immortalization dei cheratinociti colti che esprimono progerin selezionati per le cellule con normale morfologia nucleare. Nonostante le alterazioni morfologiche nei nuclei dei cheratinociti, topi che esprimono progerin nell&#39;epidermide erano normali capelli cresciuti e la guarigione delle ferite. Lo spessore dei capelli e la pelle erano normali anche dopo l&#39;attraversamento di Lmna topi null per ridurre o eliminare l&#39;espressione di normale di tipo lamins. Anche se progerin induce alterazioni significative nella morfologia nucleare dei cheratinociti che sono invertiti tramite inibizione di farnesyltransferasae, espressione epidermica non comporta alopecia o altre anomalie della pelle in genere visti nei soggetti umani con HGPS.

Espressione epidermica del prelamin troncato una causa sindrome di progeria di Hutchinson-Gilford: effetti sui cheratinociti, capelli e pelle.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.

Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition.

Syndrome de Progeria de Hutchinson-Gilford (hormones) est un trouble rare de vieillissement pr&eacute;matur&eacute; provoqu&eacute; par une mutation de novo h&eacute;t&eacute;rozygotes point G608G (GGC &gt; GGT) au sein de l&#39;exon 11 du g&egrave;ne LMNA, encodage de type lamines nucl&eacute;aires. Cette mutation provoque une d&eacute;l&eacute;tion interne de 50 acides amin&eacute;s dans l&#39;extr&eacute;mit&eacute; carboxyle de l&#39;identification du prelamin A. La prot&eacute;ine tronqu&eacute;e, progerin, conserve une cyst&eacute;ine FARN&Eacute;SYL&Eacute;E &agrave; son extr&eacute;mit&eacute; carboxyle, une modification impliqu&eacute;e dans la pathogen&egrave;se des hormones de croissance. L&#39;inhibition de la prot&eacute;ine farnesylation s&#39;est av&eacute;r&eacute;e am&eacute;liorer la morphologie anormale de nucl&eacute;aire et du ph&eacute;notype dans des mod&egrave;les cellulaires et animaux des hormones de croissance. Nous avons analys&eacute; les modifications de l&#39;expression g&eacute;nique global dans les fibroblastes des sujets humains avec des hormones de croissance et trouv&eacute; qu&#39;un r&eacute;seau de signalisation A-Rb Laget est un axe majeur de r&eacute;glementation d&eacute;fectueux. Traitement des fibroblastes avec un inhibiteur de prot&eacute;ine farnesyltransferase invers&eacute; les d&eacute;fauts d&#39;expression de g&egrave;ne. Notre &eacute;tude identifie Rb comme un facteur cl&eacute; dans la pathogen&egrave;se des hormones de croissance et sugg&egrave;re que sa modulation pourrait am&eacute;liorer le vieillissement pr&eacute;matur&eacute; et, &eacute;ventuellement, les complications du vieillissement physiologique.

D&eacute;fectueux lamin A-Rb signalisation dans le Syndrome de Hutchinson-Gilford Progeria et inversion par inhibition de farnesyltransferase.

Sindrome di Progeria di Hutchinson-Gilford (HGPS) &egrave; un disturbo raro invecchiamento precoce causato da una mutazione de novo eterozigoti punto G608G (GGC &amp;gt; GGT) nell&#39;esone 11 del gene LMNA codifica di tipo lamins nucleari. Questa mutazione provoca un&#39;eliminazione interna di 50 amminoacidi in carbossilico-terminale di prelamin A. La proteina tronca, progerin, mantiene una cisteina farnesylated al suo capolinea carbossilico, una modificazione coinvolta nella patogenesi HGPS. L&#39;inibizione della proteina farnesylation ha dimostrato di migliorare la morfologia nucleare anormale e fenotipo in modelli cellulari e animali di HGPS. Abbiamo analizzato i cambiamenti di espressione genica globale in fibroblasti di soggetti umani con HGPS e ha trovato che una rete di segnalazione A-Rb DALI &egrave; un importante asse normativo difettoso. Trattamento dei fibroblasti con un inibitore di farnesyltransferase della proteina invertito i difetti di espressione genica. Il nostro studio identifica Rb come un fattore chiave nella patogenesi HGPS e suggerisce che la modulazione potrebbe migliorare l&#39;invecchiamento prematuro e, eventualmente, le complicanze dell&#39;invecchiamento fisiologico.

Difettoso lamin A-Rb segnalazione nella sindrome di Progeria di Hutchinson-Gilford e inversione di farnesyltransferase inibizione.

Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging.

Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging.

Enfants avec le syndrome de Hutchinson-Gilford progeria (hormones de croissance) pi&egrave;ce consid&eacute;rablement acc&eacute;l&eacute;r&eacute; les maladies cardiovasculaires (MCV), causant la mort de l&#39;infarctus du myocarde ou accident vasculaire c&eacute;r&eacute;bral, &acirc;g&eacute;s de 7 &agrave; 20 ans. Nous avons entrepris la premi&egrave;re &eacute;valuation comparative histologique entre les hormones de croissance g&eacute;n&eacute;tiquement confirm&eacute;s et les maladies cardiovasculaires du vieillissement.

Pathologie cardiovasculaire dans la progeria de Hutchinson-Gilford : corr&eacute;lation avec la pathologie vasculaire du vieillissement.

I bambini con sindrome di Hutchinson-Gilford progeria (HGPS) esibiscono notevolmente accelerato malattia cardiovascolare (CVD), causando la morte per infarto del miocardio o ictus et&agrave; compresa tra i 7 e i 20 anni. Abbiamo intrapreso la prima valutazione istologica comparativa tra HGPS geneticamente confermato e CVD di invecchiamento.

Patologia cardiovascolare in progeria di Hutchinson-Gilford: correlazione con la patologia vascolare dell&#39;invecchiamento.

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as "progerin". Here, we report the isolation of naÃ¯ve multipotent skin-derived precursor (SKP) cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs) and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naÃ¯ve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases.

NaÃ¯ve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo.

Syndrome de progeria de Hutchinson-Gilford (hormones de croissance, OMIM 176670) est une affection rare caract&eacute;ris&eacute;e par vieillissement acc&eacute;l&eacute;r&eacute; segmentaire et la mort pr&eacute;coce de la maladie coronarienne ou d&#39;accident vasculaire c&eacute;r&eacute;bral. Pr&egrave;s de 90 % des personnes souffrant d&#39;hormones de croissance portent une mutation du g&egrave;ne LMNA, produisant une forme tronqu&eacute;e de l&#39;identification du prelamin A, d&eacute;nomm&eacute; &laquo; progerin &raquo; G608G exon 11. Nous rapportons ici, l&#39;isolement des cellules multipotentes d&eacute;riv&eacute;es de peau pr&eacute;curseur (SKP) na&iuml;ve des cultures de fibroblastes dermiques de donateurs d&#39;hormones de croissance. Ces cellules forment des sph&egrave;res et expriment le marqueur de la cr&ecirc;te neurale, nestin, outre les marqueurs multipotentes, OCT4, Sox2, Nanog et TG30 ; ces cellules peuvent auto-renouveler et se diff&eacute;rencient en cellules musculaires lisses (CML) et de fibroblastes. Le CML d&eacute;riv&eacute; les hormones de croissance-SKP accumule progerin nucl&eacute;aire avec une augmentation de passages. Un sous-ensemble des SKP d&#39;hormones de croissance-na&iuml;ve express progerin in vitro et in situ dans les sections de peau hormones de croissance. Il s&#39;agit de la premi&egrave;re preuve in vivo que progerin est produite dans les cellules souches adultes et implique que cette prot&eacute;ine pouvait induire &eacute;puisement de cellules souches comme un m&eacute;canisme qui contribuent au vieillissement. Notre &eacute;tude fournit une base explorer les applications th&eacute;rapeutiques pour les hormones de croissance des cellules souches et ouvre des pistes pour l&#39;&eacute;tude de la pathogen&egrave;se des autres maladies g&eacute;n&eacute;tiques.

Na&iuml;ve des cellules souches adultes provenant de patients atteints du syndrome de Hutchinson-Gilford progeria expriment des niveaux faibles de progerin in vivo.

Sindrome di progeria di Hutchinson-Gilford (HGPS, OMIM 176670) &egrave; una malattia rara caratterizzata da invecchiamento accelerato segmentale e morte precoce di malattia coronarica o ictus. Quasi il 90% dei malati di HGPS trasportano una mutazione nell&#39;esone 11 G608G LMNA, producendo una forma troncata di prelamin A, indicato come &quot;progerin&quot;. Riportiamo l&#39;isolamento delle cellule multipotenti derivate da pelle precursore (SKP) ingenuo da colture di fibroblasti dermici da donatori HGPS. Queste cellule formano sfere ed esprimono il marcatore cresta neurale, la nestina, oltre i marcatori multipotenti, OCT4, Sox2, Nanog e TG30; Queste cellule possono auto-rinnovarsi e differenziarsi in cellule muscolari lisce (SMC) e fibroblasti. SMCs derivato da HGPS-SKPs si accumulano progerin nucleare con l&#39;aumento di passaggi. Un sottoinsieme dei SKPs HGPS-na&iuml;ve esprimono progerin in vitro ed in situ in HGPS pelle sezioni. Questa &egrave; la prima prova in vivo che progerin &egrave; prodotto in cellule staminali adulte e implica che questa proteina potrebbe indurre cellule staminali esaurimento come un meccanismo che contribuiscono all&#39;invecchiamento. Il nostro studio fornisce una base esplorare le applicazioni terapeutiche per le cellule staminali HGPS e apre le vie per indagare la patogenesi di altre malattie genetiche.

Article	Year
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NaÃ¯ve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo. Biology open\| PubMed ID: 23213444	2012

Karima Djabali

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