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Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation.

ABSTRACT: Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. In this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin. In addition, reduced immunolabeling intensity of epidermal cell markers such as beta1 and alpha6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of beta4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active beta1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kindler syndrome.

SUBMITTER: Lai-Cheong JE

PROVIDER: S-EPMC2751540 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation.

Lai-Cheong Joey E JE Parsons Maddy M Tanaka Akio A Ussar Siegfried S South Andrew P AP Gomathy Sethuraman S Mee John B JB Barbaroux Jean-Baptiste JB Techanukul Tanasit T Almaani Noor N Clements Suzanne E SE Hart Ian R IR McGrath John A JA

The American journal of pathology 20090917 4

Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. In this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several bas ...[more]

PMID: 19762710

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Project description:BackgroundKindler Syndrome (KS, OMIM #173650), a rare autosomal recessive genetic disorder, is characterized by a spectrum of symptoms such as cutaneous fragility, blistering, photosensitivity, and mucosal involvement. These symptoms result from variations in the FERMT1 gene (Fermitin family member 1, OMIM: 607900), encoding kindlin-1, an essential component of focal adhesions.ObjectiveThis study aims to ascertain the potential pathogenicity of a FERMT1 variant identified in a Chinese patient and to explore the phenotypic and molecular genetic characteristics of all reported cases of Kindler Syndrome in the Chinese population.MethodsWhole-exome sequencing (WES) was performed on the patient to identify candidate variants associated with KS, and Sanger sequencing was utilized to authenticate their presence and origin. To further assess the potential impact of these genetic variants, we employed a variety of in silico prediction tools. Concurrently, a review of various databases was undertaken to ascertain and consolidate information regarding cases of KS in Chinese families.ResultsWe identified a novel likely pathogenic frameshift variant in the FERMT1 gene, specifically c.567_579delTATATATGACCCC (p.Ile190Serfs*10). The clinical presentation of this patient aligns with the diagnostic criteria for KS. The literature review reveals that the core clinical features of KS reported in the Chinese population include skin abnormalities (100%), as well as hyperkeratosis of the palms and soles (91.70%). Other clinical phenotypes encompass nail abnormalities (77.78%), abnormalities of the fingers/toes (75.00%), oral damage (70.00%), eye abnormalities (57.14%), and constipation (50.00%).ConclusionOur study enriches the genetic landscape of KS in the Chinese population and augments the understanding of phenotypic variability resulting from FERMT1 gene variants. The findings hold considerable significance for refining variant-based screening, genetic diagnosis, and comprehending the molecular pathogenesis underlying FERMT1-related disorders.

Dataset Information

Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation.

Publications

Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation.

Similar Datasets

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