AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer

Abstract

Background: Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles. PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations. It has been suggested that PPPK1 may be associated with an increased predisposition to systemic malignancies. Objectives: To evaluate the presence of AAGAB mutations in Canadian families with PPPK1 and the possible increased predisposition to systemic malignancies. Methods: Eighteen unrelated Canadian families with PPPK1 were recruited for this study. Genomic DNA was extracted from saliva and PCR amplification was performed for all AAGAB exons and exon/intron junctions. PCR products were sequenced and analyzed for mutations. A family history of malignancy was obtained from the index case and, when possible, from other family members. Results: We have identified 5 heterozygous AAGAB loss of function mutations in 11 families. The mutation c.370 C>T, p.Arg124* was the most prevalent and was identified in 6 families. A splice site mutation, c.451+3delAAGT, was identified in 2 families. The other mutations c.473delG, p.Gly158Glufs*0; c.550-551insAAT, p.Gly183*; and c.505-506 dupAA, p.Asn169Lysfs*6 were each identified in 1 family. Different cancers were reported in 11 families (Table 1 and Supplemental Figure S1). Conclusions: AAGAB mutations were found in 11 of 18 families with PPPK1. In some families there appears to be an association with cancer.

Hereditary palmoplantar keratoderma – phenotypes and mutations in 64 patients

“…The fact that no visible product with the c.73+2dup change could be detected might be explained by efficient non‐sense‐mediated decay of the deficient mRNA product. The exact normal function of AAGAB and how its mutations cause punctate PPK is not entirely known but it is involved in membrane trafficking, endocytosis and protein sorting 14 . All our patients' phenotypes matched the previously reported variable PPK punctate type 1A phenotypes 26 .…”

“…The majority of patients with AAGAB mutations (77%, 7/9) had affected relatives and onset of symptoms by age 20 (66%, 6/9) and all by the age of 41 years. The most common AAGAB mutation was c.370C>T p.(Arg124*) found in three unrelated patients 13,14 . The other mutations have not previously been associated with punctate PPK: c.(?_‐84_(73+1_74‐1)del leading to deletion of exon 1, c.73+2dup p.(?)…”

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

“…Recently, an association between PPPK1 and familial cancers, including squamous cell carcinoma, has been reported. 7 It is predicted that increased expression of EGFR in PPPK1 leads to the development of cancer.…”

“…To the best of our knowledge, 51 AAGAB mutations have been reported in affected families of different geographic and racial backgrounds (Figure 3a). [1][2][3][4][5][6][7][8][9][10][11][12][13][14] Most of the reported mutations were nonsense mutations or frameshift mutations. Six mutations affected the start codon.…”

“…1,2 To date, a total of 51 distinct AAGAB mutations have been identified in PPPK1 families from different geographic and racial backgrounds. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] However, genotype-phenotype correlations have not been defined in PPPK1. 4,5 Herein, we report four Japanese patients with PPPK1 from two families with an identical novel heterozygous AAGAB mutation.…”