Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma

Elizabeth Pohler, Ons Mamai, Jennifer Hirst, Mozheh Zamiri, Helen Horn, Toshifumi Nomura, Alan D Irvine, Benvon Moran, Neil J Wilson, Frances J D Smith, Christabelle S M Goh, Aileen Sandilands, Christian Cole, Geoffrey J Barton, Alan T Evans, Hiroshi Shimizu, Masashi Akiyama, Mitsuhiro Suehiro, Izumi Konohana, Mohammad Shboul & 12 others Sebastien Teissier, Lobna Boussofara, Mohamed Denguezli, Ali Saad, Moez Gribaa, Patricia J Dopping-Hepenstal, John A McGrath, Sara J Brown, David R Goudie, Bruno Reversade, Colin S Munro, W H Irwin McLean

    Research output: Contribution to journalArticle

    42 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)1272-1276
    Number of pages5
    JournalNature Genetics
    Volume44
    Issue number11
    DOIs
    Publication statusPublished - Nov 2012

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    Palmoplantar Keratoderma
    Haploinsufficiency
    Epidermal Growth Factor Receptor
    Carrier Proteins
    Vesicular Transport Adaptor Proteins
    rab GTP-Binding Proteins
    Growth Factor Receptors
    Keratinocytes
    Epidermis
    Cell Division
    Tyrosine
    Proteins
    Immunohistochemistry
    Phosphorylation
    Cell Proliferation
    Mutation
    Membranes

    Keywords

    • LOCUS
    • EGFR
    • MEMBRANE
    • IDENTIFICATION
    • ENDOCYTIC TRAFFICKING
    • PROTEINS
    • DESMOPLAKIN
    • MUTATIONS
    • GROWTH-FACTOR RECEPTOR
    • OCCURS

    Cite this

    Pohler, Elizabeth ; Mamai, Ons ; Hirst, Jennifer ; Zamiri, Mozheh ; Horn, Helen ; Nomura, Toshifumi ; Irvine, Alan D ; Moran, Benvon ; Wilson, Neil J ; Smith, Frances J D ; Goh, Christabelle S M ; Sandilands, Aileen ; Cole, Christian ; Barton, Geoffrey J ; Evans, Alan T ; Shimizu, Hiroshi ; Akiyama, Masashi ; Suehiro, Mitsuhiro ; Konohana, Izumi ; Shboul, Mohammad ; Teissier, Sebastien ; Boussofara, Lobna ; Denguezli, Mohamed ; Saad, Ali ; Gribaa, Moez ; Dopping-Hepenstal, Patricia J ; McGrath, John A ; Brown, Sara J ; Goudie, David R ; Reversade, Bruno ; Munro, Colin S ; McLean, W H Irwin. / Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. In: Nature Genetics. 2012 ; Vol. 44, No. 11. pp. 1272-1276.
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    title = "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma",
    abstract = "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.",
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    author = "Elizabeth Pohler and Ons Mamai and Jennifer Hirst and Mozheh Zamiri and Helen Horn and Toshifumi Nomura and Irvine, {Alan D} and Benvon Moran and Wilson, {Neil J} and Smith, {Frances J D} and Goh, {Christabelle S M} and Aileen Sandilands and Christian Cole and Barton, {Geoffrey J} and Evans, {Alan T} and Hiroshi Shimizu and Masashi Akiyama and Mitsuhiro Suehiro and Izumi Konohana and Mohammad Shboul and Sebastien Teissier and Lobna Boussofara and Mohamed Denguezli and Ali Saad and Moez Gribaa and Dopping-Hepenstal, {Patricia J} and McGrath, {John A} and Brown, {Sara J} and Goudie, {David R} and Bruno Reversade and Munro, {Colin S} and McLean, {W H Irwin}",
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    Pohler, E, Mamai, O, Hirst, J, Zamiri, M, Horn, H, Nomura, T, Irvine, AD, Moran, B, Wilson, NJ, Smith, FJD, Goh, CSM, Sandilands, A, Cole, C, Barton, GJ, Evans, AT, Shimizu, H, Akiyama, M, Suehiro, M, Konohana, I, Shboul, M, Teissier, S, Boussofara, L, Denguezli, M, Saad, A, Gribaa, M, Dopping-Hepenstal, PJ, McGrath, JA, Brown, SJ, Goudie, DR, Reversade, B, Munro, CS & McLean, WHI 2012, 'Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma', Nature Genetics, vol. 44, no. 11, pp. 1272-1276. https://doi.org/10.1038/ng.2444

    Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. / Pohler, Elizabeth; Mamai, Ons; Hirst, Jennifer; Zamiri, Mozheh; Horn, Helen; Nomura, Toshifumi; Irvine, Alan D; Moran, Benvon; Wilson, Neil J; Smith, Frances J D; Goh, Christabelle S M; Sandilands, Aileen; Cole, Christian; Barton, Geoffrey J; Evans, Alan T; Shimizu, Hiroshi; Akiyama, Masashi; Suehiro, Mitsuhiro; Konohana, Izumi; Shboul, Mohammad; Teissier, Sebastien; Boussofara, Lobna; Denguezli, Mohamed; Saad, Ali; Gribaa, Moez; Dopping-Hepenstal, Patricia J; McGrath, John A; Brown, Sara J; Goudie, David R; Reversade, Bruno; Munro, Colin S; McLean, W H Irwin (Lead / Corresponding author).

    In: Nature Genetics, Vol. 44, No. 11, 11.2012, p. 1272-1276.

    Research output: Contribution to journalArticle

    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

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    U2 - 10.1038/ng.2444

    DO - 10.1038/ng.2444

    M3 - Article

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    SP - 1272

    EP - 1276

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

    IS - 11

    ER -