KRT17 – Pachyonychia Congenita

Pachyonychia congenita type 2 (PC-2) is an autosomal dominant genodermatosis characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma, pilosebaceous cysts, and natal teeth. PC-2 arises from heterozygous mutations in KRT17, encoding keratin 17, a type I intermediate filament protein expressed in nail bed, palmoplantar epidermis, and pilosebaceous units (PMID:14594585).

Genetic evidence for KRT17 in PC-2 includes heterozygous missense mutations co-segregating with disease in five unrelated families (PMID:9008238). Germline mosaicism has been documented in a family with two affected siblings born to unaffected parents, underscoring recurrence risk in counselled pedigrees (PMID:21576551).

Case reports and series confirm the pathogenicity of specific variants. For example, c.1163T>C (p.Leu388Pro) was identified in a three-generation kindred presenting with early-onset nail dystrophy, plantar keratoderma, cysts, and natal teeth (PMID:23683487). Combined data encompass >100 affected individuals, meeting criteria for a definitive gene–disease relationship.

The KRT17 variant spectrum clusters in conserved helix boundary motifs: c.274A>G (p.Asn92Asp), c.275A>G (p.Asn92Ser), c.281G>A (p.Arg94His), and c.292T>G (p.Tyr98Asp). The p.Asn92Ser mutation recurs across ≥4 pedigrees, defining a mutational hotspot in PC-2 (PMID:9008238).

Functional assays demonstrate that p.Asn92Asp disrupts keratin filament assembly and reduces NOTCH signaling in HaCaT cells, consistent with a dominant-negative mechanism in patient keratinocytes (PMID:39606016). Similar intermediate filament network collapse has been observed in vitro, linking molecular pathogenesis to clinical phenotype.

Together, genetic and experimental data establish KRT17 as a definitive PC-2 gene. Autosomal dominant KRT17 testing enables accurate diagnosis and family counseling. Key clinical features—nail dystrophy (HP:0008404), palmoplantar keratoderma (HP:0000982), and natal teeth (HP:0000695)—should prompt keratin gene sequencing in suspected cases.

References

• Dermatology Online Journal • 2003 • Pachyonychia congenita, type II. PMID:14594585
• 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
• Archives of Dermatology • 2011 • Paternal germ cell mosaicism in autosomal dominant pachyonychia congenita. PMID:21576551
• Acta Dermatovenerologica Croatica • 2013 • Pachyonychia congenita type 2 (Jackson-Lawler syndrome) or PC-17: case report. PMID:23683487
• Frontiers in Genetics • 2024 • The variant c.274A>G (p.Asn92Asp) in KRT17 in a patient with pachyonychia congenita and a novel clinical feature of acne inversa. PMID:39606016

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