KRT17 – Sebocystomatosis

Keratin 17 (KRT17) is robustly implicated in sebocystomatosis (steatocystoma multiplex) via an autosomal dominant mechanism. Affected individuals develop multiple pilosebaceous cysts typically in adolescence or early adulthood. The overall clinical validity of the KRT17–sebocystomatosis association is Strong, supported by at least 6 unrelated probands (PMID:9008238, PMID:9767294), segregation in two multi-generation kindreds (PMID:9008238, PMID:9767294), and concordant functional predictions. No studies to date have refuted this association.

Genetic evidence arises from two small families diagnosed with steatocystoma multiplex carrying heterozygous KRT17 missense variants that co-segregate with disease (PMID:9008238, PMID:9767294). Across these families and four additional sporadic cases, six probands harbor pathogenic KRT17 alleles. Variant spectrum is dominated by missense changes affecting the 1A helix boundary motif of K17, consistent with dominant-negative effects on intermediate filament assembly.

Four independent case reports describe sporadic steatocystoma multiplex without family history, each hypothesized to involve de novo KRT17 variation (PMID:18627715, PMID:24365012, PMID:31915618, PMID:33088817). Although most lesions are asymptomatic, suppurative forms arise after minor trauma. These reports underscore variable expressivity and identify rare anatomical sites.

The variant spectrum includes at least two founder or recurrent alleles: c.292T>G (p.Tyr98Asp) and c.281G>A (p.Arg94His), both in the conserved rod domain. In total, eight distinct KRT17 missense variants have been reported in steatocystoma and related pachyonychia congenita type 2 phenotypes. No truncating or deep-intronic variants have been documented to date.

Functional evidence is Moderate: computational analyses in KVarPredDB predict destabilization of the K17 coiled-coil heterodimer and loss of inter-chain interactions for key missense variants (PMID:33287903). These in silico data align with the dominant-negative model established for other keratinopathies. No in vivo knockout or rescue models have been reported for steatocystoma multiplex.

Integration of genetic and functional findings supports a dominant-negative mechanism whereby KRT17 missense mutations disrupt keratin filament networks in sebaceous glands, leading to cyst formation. The evidence reaches the ClinGen cap for genetic data and is strengthened by consistent computational predictions. KRT17 variant testing has clear diagnostic utility for individuals with familial or early-onset steatocystoma multiplex and may guide genetic counseling and targeted therapies.

References

• The Journal of Investigative Dermatology • 1997 • Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex PMID:9008238
• The British Journal of Dermatology • 1998 • Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2 PMID:9767294
• Human Genomics • 2020 • KVarPredDB: a database for predicting pathogenicity of missense sequence variants of keratin genes associated with genodermatoses PMID:33287903

Evidence Based Scoring (AI generated)