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, K Eckl, H C Hennies, O Sarig, D Goldsher, B Meilik, A Ishida-Yamamoto, M Horowitz, E Sprecher

Research output: Contribution to journalArticle

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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)610-616
Number of pages7
JournalBritish Journal of Dermatology
Volume164
Issue number3
DOIs
Publication statusPublished - Mar 2011
Externally publishedYes

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Ichthyosis
Mutation
Cell Culture Techniques
Agenesis of Corpus Callosum
SNARE Proteins
Keratinocytes
Mutagenesis
Transfection
Down-Regulation

Cite this

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. British Journal of Dermatology, 164(3), 610-616. 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, K ; 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: British Journal of Dermatology. 2011 ; Vol. 164, No. 3. pp. 610-616.
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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.",
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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', British Journal of Dermatology, vol. 164, no. 3, pp. 610-616. 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, K; Hennies, H C; Sarig, O; Goldsher, D; Meilik, B; Ishida-Yamamoto, A; Horowitz, M; Sprecher, E.

In: British Journal of Dermatology, Vol. 164, No. 3, 03.2011, p. 610-616.

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, K

AU - Hennies, H C

AU - Sarig, O

AU - Goldsher, D

AU - Meilik, B

AU - Ishida-Yamamoto, A

AU - Horowitz, M

AU - Sprecher, E

N1 - © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

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.

KW - Blotting, Western

KW - Cells, Cultured

KW - Female

KW - Humans

KW - Infant

KW - Keratoderma, Palmoplantar

KW - Male

KW - Mutation

KW - Neurocutaneous Syndromes

KW - Qb-SNARE Proteins

KW - Qc-SNARE Proteins

KW - RNA, Messenger

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Sequence Analysis, DNA

KW - Case Reports

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1111/j.1365-2133.2010.10133.x

M3 - Article

VL - 164

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EP - 616

JO - British Journal of Dermatology

JF - British Journal of Dermatology

SN - 0007-0963

IS - 3

ER -

Fuchs-Telem D, Stewart H, Rapaport D, Nousbeck J, Gat A, Gini M et al. CEDNIK syndrome results from loss-of-function mutations in SNAP29. British Journal of Dermatology. 2011 Mar;164(3):610-616. https://doi.org/10.1111/j.1365-2133.2010.10133.x