AAGAB – Punctate Palmoplantar Keratoderma Type 1

Punctate palmoplantar keratoderma type 1 (PPKP1) is a rare autosomal dominant keratinization disorder characterized by multiple hyperkeratotic papules on the palms and soles. The AAGAB (HGNC:25662) gene has been implicated as the causative locus for PPKP1 (MONDO:0019332) through heterozygous loss‐of‐function and missense mutations in multiple unrelated families spanning diverse populations.

Initial evidence emerged from a Japanese woman in whom a novel frameshift variant c.195_198del4 (p.Lys66PhefsTer43) was identified, establishing AAGAB haploinsufficiency as a disease mechanism (PMID:25919143). Subsequent familial studies described four affected individuals across two Japanese pedigrees carrying the heterozygous missense change c.844G>A (p.Glu282Lys), demonstrating perfect cosegregation and suggesting a milder, sole-sole phenotype (PMID:34535911).

Broader replication includes three unrelated families with recurrent AAGAB variants, reinforcing the dominant inheritance and phenotypic consistency (PMID:28239884), and a Canadian cohort of 18 families in which 11 harbored loss‐of‐function alleles—most notably the recurrent nonsense variant c.370C>T (p.Arg124Ter) in six kindreds and diverse splice and frameshift mutations in others—suggesting no clear genotype-phenotype correlation but a recurring hotspot (PMID:31526046).

All reported variants are consistent with an autosomal dominant mode of inheritance with extensive segregation across at least 17 families and 19 affected individuals. The variant spectrum comprises frameshift, nonsense, splice‐site, and missense changes, indicating loss of function as the primary pathogenic mechanism. No conflicting or refuting evidence has been reported to date.

Functional data are limited to genetic predictions of haploinsufficiency; mechanistic studies or in vitro/in vivo models of AAGAB deficiency are lacking. However, the marked clinical improvement with systemic retinoids, including low-dose etretinate, supports a pathogenesis-based therapeutic approach, highlighting the role of keratinocyte differentiation pathways in PPKP1.

In summary, heterozygous pathogenic variants in AAGAB have been definitively linked to PPKP1 with strong genetic replication and a clear loss-of-function mechanism. Clinical testing for AAGAB variants should be considered in patients with punctate palmoplantar keratoderma, and systemic retinoids represent a promising treatment modality.

References

• The Journal of dermatology • 2015 • Low-dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work. PMID:25919143
• The Journal of dermatology • 2021 • Only plantar lesion of punctate palmoplantar keratoderma with a novel missense mutation in the AAGAB gene: Two Japanese familial case reports and review of reported mutations. PMID:34535911
• Clinical and experimental dermatology • 2017 • Mutations in AAGAB underlie autosomal dominant punctate palmoplantar keratoderma. PMID:28239884
• Journal of cutaneous medicine and surgery • 2020 • AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer. PMID:31526046

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