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Striate palmoplantar keratoderma is an autosomal dominant disorder characterized by linear hyperkeratotic plaques on the palms and soles with normal desmosome numbers but attenuated inner plaques and midline structures. Histopathology shows finer intermediate filaments in suprabasal keratinocytes and electron microscopy reveals weakened keratin filament networks.
Genetic linkage analysis in a four‐generation British family demonstrated significant linkage to chromosome 12q (maximum two‐point lod 3.496) with a heterozygous frameshift mutation in KRT1 (c.1628del (p.Gly543fs)) segregating with disease in eight affected relatives ([PMID:11982762]). A separate case report of an elderly patient with similar clinical and electron microscopic features supports genetic heterogeneity but underscores KRT1’s role in striate palmoplantar keratoderma ([PMID:18627762]).
The disorder follows an autosomal dominant inheritance pattern, with the identified KRT1 frameshift variant predicting a truncated V2 domain and gain of a novel 70‐amino‐acid peptide. This mutation likely acts via a dominant‐negative mechanism disrupting keratin intermediate filament assembly.
Functional assays using in vitro expression of the mutant KRT1 V2 domain in keratinocytes demonstrated its essential role in filament network formation; loss of the glycine loop motif led to aberrant filament aggregation and ultrastructural abnormalities that mirror patient skin findings ([PMID:11982762]).
No conflicting evidence has been reported for KRT1 in striate palmoplantar keratoderma, and the concordance between genetic linkage, variant segregation, and functional disruption provides robust support for a causal relationship. Additional case series exceed the ClinGen scoring maximum but reinforce KRT1 as a primary diagnostic target.
Key Take-home: KRT1 mutation screening is clinically useful for molecular diagnosis and genetic counseling in families with striate palmoplantar keratoderma.
Gene–Disease AssociationModerateOne four‐generation family with significant linkage (lod 3.496) and segregation plus functional concordance ([PMID:11982762]) Genetic EvidenceLimitedSingle kindred with a heterozygous frameshift variant (c.1628del (p.Gly543fs)) segregating in four generations ([PMID:11982762]) Functional EvidenceModerateExpression studies in keratinocytes demonstrate the V2 domain’s requirement for filament assembly, correlating with histological abnormalities ([PMID:11982762]) |