KRT14 – Dermatopathia Pigmentosa Reticularis

Dermatopathia pigmentosa reticularis (DPR) is a rare autosomal dominant ectodermal dysplasia characterized by generalized reticulate hyperpigmentation, onychodystrophy, palmoplantar keratoderma, and wiry scalp hair. DPR results from germline mutations in KRT14 and manifests with variable expressivity across kindreds (PMID:19040520).

Recurrent missense and loss-of-function variants in KRT14 underlie DPR. An unrelated Malay patient harbored the recurrent hotspot c.373C>T (p.Arg125Cys) variant, while two affected Saudi brothers also carried this missense change (PMID:19040520, PMID:27512211). Linkage analysis across one DPR and four Naegeli–Franceschetti–Jadassohn syndrome families yielded a maximal LOD score of 8.3 at 17q11.2–q21, identifying heterozygous truncating mutations (c.19C>T (p.Gln7Ter), c.17del (p.Arg6fs), c.54C>A (p.Cys18Ter)) in the nonhelical head (E1/V1) domain of KRT14 that segregate with disease (PMID:16960809).

The variant spectrum in DPR comprises the missense hotspot p.Arg125Cys and multiple head‐domain truncating alleles predicted to cause early translation termination. These pathogenic alleles cluster in the E1/V1 domain, distinct from rod‐domain mutations causing epidermolysis bullosa simplex.

Inheritance is autosomal dominant, with segregation of pathogenic KRT14 alleles in three DPR kindreds (one sporadic case, one sibship of two, one multiplex family) and no evidence for recessive transmission.

Functional studies demonstrate that E1/V1‐domain truncating mutations result in K14 haploinsufficiency. In vitro assays show increased TNF-α–induced apoptotic susceptibility in keratinocytes with reduced K14 levels, and ultrastructural analyses reveal elevated basal‐layer apoptosis and absent dermatoglyphics, concordant with patient phenotype (PMID:16960809, PMID:18049449).

Collectively, genetic and experimental evidence support a Moderate clinical validity for the KRT14–DPR association. Haploinsufficiency of KRT14 is the predominant pathogenic mechanism. Clinical testing of KRT14 is recommended for definitive diagnosis of DPR.

References

• Clinical and experimental dermatology • 2009 • A case of dermatopathia pigmentosa reticularis with wiry scalp hair and digital fibromatosis resulting from a recurrent KRT14 mutation. PMID:19040520
• Indian journal of dermatology • 2016 • Dermatopathia Pigmentosa Reticularis: Report of a New Cases and Literature Review. PMID:27512211
• American journal of human genetics • 2006 • Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. PMID:16960809

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