Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma

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Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics1,2,3. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin–binding protein p34, located at a previously linked locus at 15q22. α- and γ-adaptin–binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation.

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Figure 1: Clinical and histological features of punctate PPK.
Figure 2: Identification of mutations in AAGAB in families with PPKP1.
Figure 3: AAGAB is expressed in skin and keratinocytes and its depletion leads to increased cell numbers over time.
Figure 4: p34 associates with AP-1 and AP-2 in the cytosol.
Figure 5: Transmission electron microscopy of lesional plantar skin shows vesicle abnormalities within basal keratinocytes.
Figure 6: Knockdown of AAGAB greatly increases EGFR protein expression.

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The authors dedicate this paper to their erstwhile colleague, the late dermatologist and cell biologist Susan M. Morley, who treated some of the individuals studied here. We thank M. Robinson and C. Watts for insightful discussions, I. Nathke and I. Newton for their help with protein blot quantification and Tayside Tissue Bank, Dundee for providing skin samples. Specialist Sequencing and Bioinformatics Services were provided by The Eastern Sequence and Informatics Hub (EASIH) at the University of Cambridge, which is supported by the National Institute for Health Research and the Cambridge Biomedical Research Centre. This work was supported by a Wellcome Trust Programme Grant (092530/Z/10/Z) to W.H.I.M., A.D.I. and G.J.B., a Wellcome Trust Strategic Award (098439/Z/12/Z) to W.H.I.M., G.J.B. and J.A.M., a project grant from the Pachyonychia Congenita Project to F.J.D.S. and a strategic positioning fund for Genetic Orphan Diseases from A*STAR. O.M. was funded by an A*STAR Research Attachment Program (ARAP), and B.R. is a fellow of the Branco Weiss Foundation.

Author information

W.H.I.M. designed the study. M.Z., H.H., T.N., A.D.I., B.M., H.S., M.A., M. Suehiro, I.K., L.B., M.D., A. Saad, M.G., O.M. and C.S.M. diagnosed subjects and collected clinical samples and phenotype data. E.P., O.M., N.J.W., M. Shboul and S.T. conducted genotyping, mapping and sequencing. J.H. and E.P. performed protein functional studies. J.H. generated the polyclonal antibodies to p34. C.C. and G.J.B. carried out next-generation sequencing bioinformatics. A.T.E. performed the dermatopathology analysis. P.J.D.-H. and J.A.M. performed ultrastructural analysis. S.J.B., O.M. and A. Sandilands provided tissue samples. C.S.M.G. and A. Sandilands performed the tissue expression analysis. D.R.G. performed statistical genetics. W.H.I.M., E.P., J.H., B.R., J.A.M., C.S.M. and F.J.D.S. wrote the manuscript.

Correspondence to W H Irwin McLean.

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Pohler, E., Mamai, O., Hirst, J. et al. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat Genet 44, 1272–1276 (2012) doi:10.1038/ng.2444

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