FERMT1 – Kindler syndrome

Kindler syndrome (KS) is an autosomal recessive genodermatosis characterized by acral blistering in infancy, marked photosensitivity, progressive poikiloderma, skin atrophy, mucosal stenoses, and a heightened risk of squamous cell carcinoma. Biallelic loss-of-function variants in FERMT1, encoding kindlin-1—a focal adhesion protein linking integrins to the actin cytoskeleton—underlie KS pathogenesis (PMID:12668616).

Inheritance is strictly autosomal recessive, with over 150 affected individuals reported, including 62 patients in a multicenter cohort (PMID:21936020) and 91 adults in a retrospective study assessing squamous cell carcinoma risk (PMID:31340837). Segregation analysis in a large Palestinian pedigree demonstrated cosegregation of FERMT1 variants in 18 affected relatives (PMID:25515598).

The variant spectrum is dominated by nonsense, frameshift, and splice-site mutations predicted to abolish kindlin-1 expression. A recurrent nonsense allele, c.328C>T (p.Arg110Ter), has been identified homozygously in siblings with late diagnosis (PMID:20938162). Founder mutations such as c.676dup have been reported in Pakistani and Italian cohorts, facilitating targeted screening in these populations.

Loss of kindlin-1 impairs keratinocyte adhesion, spreading, and migration via disrupted integrin signaling. C-terminal truncations (e.g., exon-skipping due to c.1718+1G>A) produce nonfunctional proteins that escape degradation but fail to support focal adhesion stability (PMID:18652585; PMID:21146372). Kindlin-1–deficient keratinocytes show abnormal β1-integrin glycosylation and reduced surface expression, reversible upon wild-type FERMT1 complementation (PMID:23776470).

In vivo, zebrafish harboring a loss-of-function kindlin-1 mutation manifest epidermal fragility and fin rupturing, mirroring human KS and confirming a conserved adhesion defect (PMID:23549420). Rescue experiments with chemical chaperone sodium-phenylbutyrate in keratinocytes carrying a hypomorphic p.Arg100del allele restored kindlin-1 levels and cellular spreading, highlighting therapeutic potential (PMID:26827766).

No studies have refuted the FERMT1–KS association. Genotype–phenotype correlations suggest that missense and in-frame deletions may yield milder phenotypes, but overall clinical variability is influenced by environmental modifiers and potential genetic modifiers (PMID:21936020).

Definitive genetic and functional evidence support FERMT1 testing in patients with blistering, photosensitivity, and poikiloderma for accurate diagnosis, family counseling, and surveillance for skin cancer. Early molecular confirmation enables precision management and informs emerging chaperone-based therapies.

References

• Human molecular genetics • 2003 • Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome PMID:12668616
• Human mutation • 2011 • Kindler syndrome: extension of FERMT1 mutational spectrum and natural history PMID:21936020
• Orphanet journal of rare diseases • 2019 • Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients PMID:31340837
• European journal of dermatology • 2015 • Kindler syndrome with severe mucosal involvement in a large Palestinian pedigree PMID:25515598
• Dermatology (Basel) • 2010 • Mild clinical phenotype of Kindler syndrome associated with late diagnosis and skin cancer PMID:20938162
• The British journal of dermatology • 2008 • C-terminally truncated kindlin-1 leads to abnormal adhesion and migration of keratinocytes PMID:18652585
• The Journal of investigative dermatology • 2008 • Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome PMID:18528435
• PloS One • 2013 • Kindlin-1 regulates integrin dynamics and adhesion turnover PMID:23776470
• Anais brasileiros de dermatologia • 2013 • Sporadic Kindler syndrome with a novel mutation PMID:24346923
• Journal of Zhejiang University. Science. B • 2015 • A novel large deletion mutation of FERMT1 gene in a Chinese patient with Kindler syndrome PMID:26537214

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