CEDNIK syndrome results from loss-of-function mutations in SNAP29.

D Fuchs-Telem, H Stewart, D Rapaport, J Nousbeck, A Gat, M Gini, Y Lugassy, S Emmert, Katja Eckl, H C Hennies, O Sarig, D Goldsher, B Meilik, A Ishida-Yamamoto, M Horowitz, E Sprecher

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Abstract

BACKGROUND CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. OBJECTIVES To delineate the molecular consequences of disease-causing mutations in SNAP29. METHODS We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. RESULTS We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. CONCLUSIONS The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.
Original languageEnglish
Pages (from-to)610-6
JournalThe British journal of dermatology
Volume164
Issue number3
DOIs
Publication statusPublished - Mar 2011

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Ichthyosis
Mutation
Cell Culture Techniques
Agenesis of Corpus Callosum
SNARE Proteins
Keratinocytes
Mutagenesis
Transfection
Down-Regulation
Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome
In Vitro Techniques

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Fuchs-Telem, D., Stewart, H., Rapaport, D., Nousbeck, J., Gat, A., Gini, M., ... Sprecher, E. (2011). CEDNIK syndrome results from loss-of-function mutations in SNAP29. The British journal of dermatology, 164(3), 610-6. https://doi.org/10.1111/j.1365-2133.2010.10133.x
Fuchs-Telem, D ; Stewart, H ; Rapaport, D ; Nousbeck, J ; Gat, A ; Gini, M ; Lugassy, Y ; Emmert, S ; Eckl, Katja ; Hennies, H C ; Sarig, O ; Goldsher, D ; Meilik, B ; Ishida-Yamamoto, A ; Horowitz, M ; Sprecher, E. / CEDNIK syndrome results from loss-of-function mutations in SNAP29. In: The British journal of dermatology. 2011 ; Vol. 164, No. 3. pp. 610-6.
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abstract = "BACKGROUND CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. OBJECTIVES To delineate the molecular consequences of disease-causing mutations in SNAP29. METHODS We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. RESULTS We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. CONCLUSIONS The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.",
author = "D Fuchs-Telem and H Stewart and D Rapaport and J Nousbeck and A Gat and M Gini and Y Lugassy and S Emmert and Katja Eckl and Hennies, {H C} and O Sarig and D Goldsher and B Meilik and A Ishida-Yamamoto and M Horowitz and E Sprecher",
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Fuchs-Telem, D, Stewart, H, Rapaport, D, Nousbeck, J, Gat, A, Gini, M, Lugassy, Y, Emmert, S, Eckl, K, Hennies, HC, Sarig, O, Goldsher, D, Meilik, B, Ishida-Yamamoto, A, Horowitz, M & Sprecher, E 2011, 'CEDNIK syndrome results from loss-of-function mutations in SNAP29.', The British journal of dermatology, vol. 164, no. 3, pp. 610-6. https://doi.org/10.1111/j.1365-2133.2010.10133.x

CEDNIK syndrome results from loss-of-function mutations in SNAP29. / Fuchs-Telem, D; Stewart, H; Rapaport, D; Nousbeck, J; Gat, A; Gini, M; Lugassy, Y; Emmert, S; Eckl, Katja; Hennies, H C; Sarig, O; Goldsher, D; Meilik, B; Ishida-Yamamoto, A; Horowitz, M; Sprecher, E.

In: The British journal of dermatology, Vol. 164, No. 3, 03.2011, p. 610-6.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CEDNIK syndrome results from loss-of-function mutations in SNAP29.

AU - Fuchs-Telem, D

AU - Stewart, H

AU - Rapaport, D

AU - Nousbeck, J

AU - Gat, A

AU - Gini, M

AU - Lugassy, Y

AU - Emmert, S

AU - Eckl, Katja

AU - Hennies, H C

AU - Sarig, O

AU - Goldsher, D

AU - Meilik, B

AU - Ishida-Yamamoto, A

AU - Horowitz, M

AU - Sprecher, E

PY - 2011/3

Y1 - 2011/3

N2 - BACKGROUND CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. OBJECTIVES To delineate the molecular consequences of disease-causing mutations in SNAP29. METHODS We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. RESULTS We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. CONCLUSIONS The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.

AB - BACKGROUND CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. OBJECTIVES To delineate the molecular consequences of disease-causing mutations in SNAP29. METHODS We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. RESULTS We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. CONCLUSIONS The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.

U2 - 10.1111/j.1365-2133.2010.10133.x

DO - 10.1111/j.1365-2133.2010.10133.x

M3 - Article

VL - 164

SP - 610

EP - 616

JO - British Journal of Dermatology

JF - British Journal of Dermatology

SN - 0007-0963

IS - 3

ER -