Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma

TY - JOUR

T1 - Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma

AU - Pohler, Elizabeth

AU - Mamai, Ons

AU - Hirst, Jennifer

AU - Zamiri, Mozheh

AU - Horn, Helen

AU - Nomura, Toshifumi

AU - Irvine, Alan D

AU - Moran, Benvon

AU - Wilson, Neil J

AU - Smith, Frances J D

AU - Goh, Christabelle S M

AU - Sandilands, Aileen

AU - Cole, Christian

AU - Barton, Geoffrey J

AU - Evans, Alan T

AU - Shimizu, Hiroshi

AU - Akiyama, Masashi

AU - Suehiro, Mitsuhiro

AU - Konohana, Izumi

AU - Shboul, Mohammad

AU - Teissier, Sebastien

AU - Boussofara, Lobna

AU - Denguezli, Mohamed

AU - Saad, Ali

AU - Gribaa, Moez

AU - Dopping-Hepenstal, Patricia J

AU - McGrath, John A

AU - Brown, Sara J

AU - Goudie, David R

AU - Reversade, Bruno

AU - Munro, Colin S

AU - McLean, W H Irwin

PY - 2012/11

Y1 - 2012/11

N2 - Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics. 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 a- and ?-adaptin-binding protein p34, located at a previously linked locus at 15q22. a- and ?-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.

AB - Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics. 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 a- and ?-adaptin-binding protein p34, located at a previously linked locus at 15q22. a- and ?-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.

KW - LOCUS

KW - EGFR

KW - MEMBRANE

KW - IDENTIFICATION

KW - ENDOCYTIC TRAFFICKING

KW - PROTEINS

KW - DESMOPLAKIN

KW - MUTATIONS

KW - GROWTH-FACTOR RECEPTOR

KW - OCCURS

UR - https://www.scopus.com/pages/publications/84868205726

U2 - 10.1038/ng.2444

DO - 10.1038/ng.2444

M3 - Article

C2 - 23064416

SN - 1061-4036

VL - 44

SP - 1272

EP - 1276

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -