Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma



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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes


NCBI Reference Sequence


  1. Itin, P.H. & Fistarol, S.K. Palmoplantar keratodermas. Clin. Dermatol. 23, 15–22 (2005).

    Article  Google Scholar 

  2. Stevens, H.P. et al. Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Arch. Dermatol. 132, 640–651 (1996).

    Article  CAS  Google Scholar 

  3. Kelsell, D.P. & Stevens, H.P. The palmoplantar keratodermas: much more than palms and soles. Mol. Med. Today 5, 107–113 (1999).

    Article  CAS  Google Scholar 

  4. Emmert, S. et al. 47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. Eur. J. Dermatol. 13, 16–20 (2003).

    PubMed  Google Scholar 

  5. Martinez-Mir, A. et al. Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24. J. Med. Genet. 40, 872–878 (2003).

    Article  CAS  Google Scholar 

  6. Gao, M. et al. Refined localization of a punctate palmoplantar keratoderma gene to a 5.06-cM region at 15q22.2–15q22.31. Br. J. Dermatol. 152, 874–878 (2005).

    Article  CAS  Google Scholar 

  7. Jung, E.G. Acrokeratoelastoidosis. Humangenetik 17, 357–358 (1973).

    CAS  PubMed  Google Scholar 

  8. Zhang, X.J. et al. Identification of a locus for punctate palmoplantar keratodermas at chromosome 8q24.13–8q24.21. J. Invest. Dermatol. 122, 1121–1125 (2004).

    Article  CAS  Google Scholar 

  9. El Amri, I. et al. Clinical and genetic characteristics of Buschke-Fischer-Brauer's disease in a Tunisian family. Ann. Dermatol. Venereol. 137, 269–275 (2010).

    Article  CAS  Google Scholar 

  10. Page, L.J., Sowerby, P.J., Lui, W.W. & Robinson, M.S. γ-synergin: an EH domain–containing protein that interacts with γ-adaptin. J. Cell Biol. 146, 993–1004 (1999).

    Article  CAS  Google Scholar 

  11. Boukamp, P. et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol. 106, 761–771 (1988).

    Article  CAS  Google Scholar 

  12. Robinson, M.S. & Bonifacino, J.S. Adaptor-related proteins. Curr. Opin. Cell Biol. 13, 444–453 (2001).

    Article  CAS  Google Scholar 

  13. Robinson, M.S. Adaptable adaptors for coated vesicles. Trends Cell Biol. 14, 167–174 (2004).

    Article  CAS  Google Scholar 

  14. Horgan, C.P. & McCaffrey, M.W. Rab GTPases and microtubule motors. Biochem. Soc. Trans. 39, 1202–1206 (2011).

    Article  CAS  Google Scholar 

  15. Ceresa, B.P. Regulation of EGFR endocytic trafficking by rab proteins. Histol. Histopathol. 21, 987–993 (2006).

    CAS  PubMed  Google Scholar 

  16. Rappoport, J.Z. & Simon, S.M. Endocytic trafficking of activated EGFR is AP-2 dependent and occurs through preformed clathrin spots. J. Cell Sci. 122, 1301–1305 (2009).

    Article  CAS  Google Scholar 

  17. Downward, J., Parker, P. & Waterfield, M.D. Autophosphorylation sites on the epidermal growth factor receptor. Nature 311, 483–485 (1984).

    Article  CAS  Google Scholar 

  18. Sousa, L.P. et al. Suppression of EGFR endocytosis by dynamin depletion reveals that EGFR signaling occurs primarily at the plasma membrane. Proc. Natl. Acad. Sci. USA 109, 4419–4424 (2012).

    Article  CAS  Google Scholar 

  19. Goh, L.K., Huang, F., Kim, W., Gygi, S. & Sorkin, A. Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. J. Cell Biol. 189, 871–883 (2010).

    Article  CAS  Google Scholar 

  20. Sprecher, E. et al. A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am. J. Hum. Genet. 77, 242–251 (2005).

    Article  CAS  Google Scholar 

  21. Gissen, P. et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome. Nat. Genet. 36, 400–404 (2004).

    Article  CAS  Google Scholar 

  22. Montpetit, A. et al. Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet. 4, e1000296 (2008).

    Article  Google Scholar 

  23. Van Gele, M., Dynoodt, P. & Lambert, J. Griscelli syndrome: a model system to study vesicular trafficking. Pigment Cell Melanoma Res. 22, 268–282 (2009).

    Article  CAS  Google Scholar 

  24. Tarpey, P.S. et al. Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation. Am. J. Hum. Genet. 79, 1119–1124 (2006).

    Article  CAS  Google Scholar 

  25. Bennion, 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. 10, 587–591 (1984).

    Article  CAS  Google Scholar 

  26. Armstrong, D.K. et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum. Mol. Genet. 8, 143–148 (1999).

    Article  CAS  Google Scholar 

  27. Wan, H. et al. Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network. Br. J. Dermatol. 150, 878–891 (2004).

    Article  CAS  Google Scholar 

  28. McLean, W.H. Genetic disorders of palm skin and nail. J. Anat. 202, 133–141 (2003).

    Article  Google Scholar 

  29. Cottingham, R.W. Jr., Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

    PubMed  PubMed Central  Google Scholar 

  30. Schäffer, A.A., Gupta, S.K., Shriram, K. & Cottingham, R.W. Jr. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).

    Article  Google Scholar 

  31. Hirst, J., Miller, S.E., Taylor, M.J., von Mollard, G.F. & Robinson, M.S. EpsinR is an adaptor for the SNARE protein Vti1b. Mol. Biol. Cell 15, 5593–5602 (2004).

    Article  CAS  Google Scholar 

Download references


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

Authors and Affiliations



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.

Corresponding author

Correspondence to W H Irwin McLean.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–5 (PDF 7296 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing