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 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 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.
Centre for Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry & Nursing, University of Dundee, UK.
Elizabeth
E
Pohler
Ons
O
Mamai
Jennifer
J
Hirst
Mozheh
M
Zamiri
Helen
H
Horn
Toshifumi
T
Nomura
Alan D
AD
Irvine
Benvon
B
Moran
Neil J
NJ
Wilson
Frances J D
FJ
Smith
Christabelle S M
CS
Goh
Aileen
A
Sandilands
Christian
C
Cole
Geoffrey J
GJ
Barton
Alan T
AT
Evans
Hiroshi
H
Shimizu
Masashi
M
Akiyama
Mitsuhiro
M
Suehiro
Izumi
I
Konohana
Mohammad
M
Shboul
Sebastien
S
Teissier
Lobna
L
Boussofara
Mohamed
M
Denguezli
Ali
A
Saad
Moez
M
Gribaa
Patricia J
PJ
Dopping-Hepenstal
John A
JA
McGrath
Sara J
SJ
Brown
David R
DR
Goudie
Bruno
B
Reversade
Colin S
CS
Munro
W H Irwin
WH
McLean
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D003600:Cytosol / Q000648:ultrastructure; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057895:Haploinsufficiency; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D017499:Porokeratosis / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism
C579464:AAGAB protein, human; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D011506:Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors