Abstract

Pachyonychia congenita (PC) is a genetic disorder of keratin that presents with nail dystrophy, painful palmoplantar keratoderma, and other clinical manifestations. We investigated genotype-structurotype-phenotype correlations seen with mutations in keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17) and utilized protein structure modeling of high frequency mutations to examine the functional importance of keratin structural domains in PC pathogenesis. Participants of the International PC Research Registry underwent genetic testing and completed a standardized survey on their symptoms. Our results support prior reports associating oral leukokeratosis with KRT6A mutations, and cutaneous cysts, follicular hyperkeratosis, and natal teeth with KRT17 mutations. Painful keratoderma was prominent with KRT6A and KRT16 mutations. Nail involvement was most common in KRT6A and least common in KRT6C patients. Across keratin subtypes, patients with coil 2B mutations had greatest impairment in ambulation, and patients with coil 1A mutations reported more emotional issues. Molecular modeling demonstrated that hotspot missense mutations in PC largely disrupted hydrophobic interactions or surface charge. The former may destabilize keratin dimers/tetramers, while the latter likely interferes with higher-order keratin filament formation. Understanding pathologic alterations in keratin structure improves our knowledge of how PC genotype correlates with clinical phenotype, advancing insight into disease pathogenesis and therapeutic development.

View details for DOI 10.1016/j.jid.2021.03.035

View details for PubMedID 34116063