Portal de Periódicos da CAPES

Identification of Distinct Mutations in AAGAB in Families with Type 1 Punctate Palmoplantar Keratoderma

2014; Elsevier BV; Volume: 134; Issue: 6 Linguagem: Inglês

10.1038/jid.2014.4

1523-1747

Megan Furniss, Claire A. Higgins, Amalia Martı́nez-Mir, Liran Horev, Lynn Petukhova, Andrija Stanimirović, Jovan Miljković, Abraham Zlotogorski, Angela M. Christiano,

Wnt/β-catenin signaling in development and cancer

palmoplantar keratoderma/palmoplantar keratoderma, punctate, type 1 TO THE EDITOR Our understanding of skin biology has been greatly enhanced by studying genodermatoses, as this has guided the discovery of key genes responsible for skin function (Chamcheu et al., 2011Chamcheu J.C. Siddiqui I.A. Syed D.N. et al.Keratin gene mutations in disorders of human skin and its appendages.Arch Biochem Biophys. 2011; 508: 123-137Crossref PubMed Scopus (139) Google Scholar). Palmoplantar keratodermas (PPKs) are a group of rare, heterogeneous hereditary diseases characterized by epidermal hyperkeratosis of palmoplantar skin. They are typically classified according to their mode of inheritance or morphologic features of the disease. However, the clinical picture is often complicated by significant interfamilial and intrafamilial variation in lesional appearance (Kelsell and Stevens, 1999Kelsell D.P. Stevens H.P. The palmoplantar keratodermas: much more than palms and soles.Mol Med Today. 1999; 5: 107-113Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). In this study, we focused on punctate palmoplantar keratoderma type 1 (PPKP1), also known as punctate PPK, or Buschke–Fischer–Brauer (OMIM 148600). The inheritance of punctate PPK is commonly autosomal dominant; however, it sometimes presents as an acquired disease (Emmert et al., 2003Emmert S. Kuster W. Hennies H.C. et al.47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer.Eur J Dermatol. 2003; 13: 16-20PubMed Google Scholar). The onset of punctate PPK is usually observed between 10 and 45 years of age, with the number and severity of lesions increasing with advancing age. Lesions present as multiple small, yellow, hyperkeratotic papules with central indentation and are irregularly distributed. Typically, there is an increased confluence of lesions over areas of high pressure, such as on the soles of the feet, whereas the punctate morphology is more evident on the palms (Figure 1a). There is an absence of inflammatory changes, and only rarely are there nail findings observed in punctate PPK. Notably, punctate PPK has been reported to be associated with an increased incidence of squamous cell carcinomas, as well as early- and late-onset malignancies, such as Hodgkin’s disease, renal, breast, pancreatic, and colonic adenocarcinomas (Bennion and Patterson, 1984Bennion S.D. Patterson J.W. Keratosis punctata palmaris et plantaris and adenocarcinoma of the colon. A possible familial association of punctate keratoderma and gastrointestinal malignancy.J Am Acad Dermatol. 1984; 10: 587-591Abstract Full Text PDF PubMed Scopus (46) Google Scholar; Kelsell and Stevens, 1999Kelsell D.P. Stevens H.P. The palmoplantar keratodermas: much more than palms and soles.Mol Med Today. 1999; 5: 107-113Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Ten years ago, mutations in more than 15 genes had been identified in different forms of PPK; however, the pathogenic mutations underlying punctate PPK were unknown. We previously reported three large pedigrees from Israel and Mexico, punctate PPK, and mapped the affected locus to chromosome 15q22–24 using linkage analysis (Martinez-Mir et al., 2003Martinez-Mir A. Zlotogorski A. Londono D. et al.Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24.J Med Genet. 2003; 40: 872-878Crossref PubMed Scopus (31) Google Scholar). Recently, two groups simultaneously identified several loss-of-function mutations in a single gene, AAGAB, in multiple families of different ancestries with punctate PPK (Giehl et al., 2012Giehl K.A. Eckstein G.N. Pasternack S.M. et al.Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer.Am J Hum Genet. 2012; 91: 754-759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar; Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar). AAGAB encodes the α- and γ-adaptin-binding protein p34, and is located on chromosome 15q.22, within our previously identified linkage region (Martinez-Mir et al., 2003Martinez-Mir A. Zlotogorski A. Londono D. et al.Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24.J Med Genet. 2003; 40: 872-878Crossref PubMed Scopus (31) Google Scholar). Four subsequent studies have described mutations in AAGAB that underlie punctate PPK in several new families (Cui et al., 2013Cui H. Gao M. Wang W. et al.Six mutations in AAGAB confirm its pathogenic role in Chinese punctate palmoplantar keratoderma patients.J Invest Dermatol. 2013; 133: 2631-2634Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar; Kiritsi et al., 2013Kiritsi D. Chmel N. Arnold A.W. et al.Novel and recurrent AAGAB mutations: clinical variability and molecular consequences.J Invest Dermatol. 2013; 133: 2483-2486Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar; Li et al., 2013Li M. Yang L. Shi H. et al.Loss-of-function mutation in AAGAB in Chinese families with punctuate palmoplantar keratoderma.Br J Dermatol. 2013; 169: 168-171Crossref PubMed Scopus (12) Google Scholar; Pohler et al., 2013Pohler E. Zamiri M. Harkins C.P. et al.Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling.J Invest Dermatol. 2013; 133: 2805-2808Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). In light of these findings, we sequenced the whole AAGAB gene in our cohort of 11 families with punctate PPK (Supplementary Figures S1–S11 online). The pedigrees of PPK01–PPK03 were previously documented, in our linkage studies (Martinez-Mir et al., 2003Martinez-Mir A. Zlotogorski A. Londono D. et al.Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24.J Med Genet. 2003; 40: 872-878Crossref PubMed Scopus (31) Google Scholar). We sequenced PPK01 and PPK02, which are of Israeli and Arab-Israeli origin, for mutations in AAGAB. Further, we sequenced AAGAB in an additional nine new families with punctate PPK, which were designated PPK04–PPK12. Of these, two were from Israel, one was from Canada, and six were from Slovenia. In Slovenia, the incidence of punctate PPK is 3.3/100,000, making it extremely prevalent in this population, compared with the twofold lower incidence of 1.17/100,000 in the neighboring Croatian population (Stanimirovic et al., 1993Stanimirovic A. Kansky A. Basta-Juzbasic A. et al.Hereditary palmoplantar keratoderma, type papulosa, in Croatia.J Am Acad Dermatol. 1993; 29: 435-437Abstract Full Text PDF PubMed Scopus (28) Google Scholar; Miljkovic and Kansky, 2009Miljkovic J. Kansky A. Hereditary palmoplantar keratoderma type papulosa in Slovenia.Acta Dermatovenerol Alp Panonica Adriat. 2009; 18: 114-116PubMed Google Scholar). Download .pdf (.69 MB) Help with pdf files Supplementary Information Genomic DNA was obtained from blood samples collected following informed consent in accordance with IRB regulations at Columbia University and the Declaration of Helsinki Principles. We used Sanger Sequencing to sequence the AAGAB gene in patients from each of our families, using primers previously described for this gene (Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar). Pedigrees, sequencing results, and photographs of each family can be found in the Supplementary results. We found 7 distinct pathogenic mutations within 11 families, of which 5 are previously unreported to our knowledge (Figure 1b). These were all heterozygous, consistent with an autosomal dominant pattern of inheritance. Mutations segregated with the disease phenotype in all but one unaffected individual where a heterozygous mutation was detected. Presumably this patient had not yet manifested the phenotype (Supplementary Figure S4 online). Of the seven identified mutations (Table 1), we found one, c.481C>T: p.R161X, in four families (three from Slovenia and one from Israel). This mutation was previously described as a founder mutation in families of Croatian origin (Giehl et al., 2012Giehl K.A. Eckstein G.N. Pasternack S.M. et al.Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer.Am J Hum Genet. 2012; 91: 754-759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar), and was also observed within Scottish and Chinese families (Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar; Cui et al., 2013Cui H. Gao M. Wang W. et al.Six mutations in AAGAB confirm its pathogenic role in Chinese punctate palmoplantar keratoderma patients.J Invest Dermatol. 2013; 133: 2631-2634Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar; Kiritsi et al., 2013Kiritsi D. Chmel N. Arnold A.W. et al.Novel and recurrent AAGAB mutations: clinical variability and molecular consequences.J Invest Dermatol. 2013; 133: 2483-2486Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). Moreover, the mutation in our Canadian family, c.472delG; p.G158Efs*1, was previously found in five families of Scottish origin (Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar). To our knowledge the other five mutations identified in this study have not been reported elsewhere to date. Of these, one mutation, c.566C>G, p.S189X, was found in two families of Slovenian origin, whereas the remaining four mutations, which were all predicted to cause frameshifts in the protein, were each unique to a single family. Substantial phenotypic variability was noted between patients who carried the same mutation, ranging from very mild to extensively hyperkeratotic presentations of the disease. Although this indicates that environmental factors and personal skin care regimens may affect the degree of hyperkeratosis, it is not uncommon for dominantly inherited diseases to exhibit such variable expressivity.Table 1Summary of mutations in AAGAB gene found in 11 families with punctate PPKDNA mutationConsequence to proteinFamiliesAncestryc.481C>T1Mutation previously reported by Pohler et al., 2012, Giehl et al., 2012, Cui et al., 2013, and Kiritsi et al., 2013.p.R161XPPK04, PPK07, PPK08, PPK09Slovenian and Arab-Israelic.566C>Gp.S189XPPK05, PPK06Slovenianc.58-68delGACCAGCTGGTp.D20Pfs*2PPK02Israelic.472delG2Mutation previously reported by Pohler et al., 2012 and Pohler et al., 2013.p.G158Efs*1PPK11Canadianc.562-563insTCp.N188Sfs*3PPK01Israelic.295insGp.L99Afs*9PPK12Israelic.639delApA213Afs*29PPK10Slovenian1 Mutation previously reported by Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar, Giehl et al., 2012Giehl K.A. Eckstein G.N. Pasternack S.M. et al.Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer.Am J Hum Genet. 2012; 91: 754-759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Cui et al., 2013Cui H. Gao M. Wang W. et al.Six mutations in AAGAB confirm its pathogenic role in Chinese punctate palmoplantar keratoderma patients.J Invest Dermatol. 2013; 133: 2631-2634Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, and Kiritsi et al., 2013Kiritsi D. Chmel N. Arnold A.W. et al.Novel and recurrent AAGAB mutations: clinical variability and molecular consequences.J Invest Dermatol. 2013; 133: 2483-2486Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar.2 Mutation previously reported by Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar and Pohler et al., 2013Pohler E. Zamiri M. Harkins C.P. et al.Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling.J Invest Dermatol. 2013; 133: 2805-2808Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar. Open table in a new tab AAGAB consists of 10 exons with a coding sequence of 945 nucleotides, and it codes for the α- and γ-adaptin-binding protein p34 (Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar). p34 has a role in membrane trafficking, and as a result of AAGAB mutations, deficiencies in p34 lead to impaired endocytic recycling of EGFR proteins, which in turn leads to cellular hyperproliferation (Pohler et al., 2012Pohler E. Mamai O. Hirst J. et al.Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.Nat Genet. 2012; 44: 1272-1276Crossref PubMed Scopus (60) Google Scholar). Cellular hyperproliferation is postulated to be at least one cause of the hyperkeratotic lesions observed in punctate PPK. In summary, to our knowledge we identified five previously unreported mutations and two recurrent mutations of the AAGAB gene, which underlie punctate PPK. There are now a total of 22 mutations in AAGAB that have been identified in patients with punctate PPK. Although PPK is a rare disorder, diseases characterized by hyperkeratosis and hyperproliferation are common, and identification of the underlying cellular mechanisms in this familial keratoderma may contribute to our future ability to understand and treat the more prevalent hyperkeratotic diseases. We are very grateful to the patients and families that participated in this study. We also thank those who participated in the technical support for this study: T Waran Lalin, Y Quin, and HM Lin. This study was supported in part by funding from the NIH/NIAMS (R01-AR44924) to AMC. MF is a trainee on NIH/NIGMS T32GM082771, Medical Genetics Training Program. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid