Fuchs-Telem, D., Stewart, H., Rapaport, D., Nousbeck, J., Gat, A., Gini, M., Lugassy, Y., Emmert, S., Eckl, K.M., Hennies, Hans C., Sarig, O., Goldsher, D., Meilik, B., Ishida-Yamamoto, A., Horowitz, M. and Sprecher, E. (2011) CEDNIK syndrome results from loss-of-function mutations in SNAP29. British Journal of Dermatology, 164 (3). pp. 610-616. ISSN 0007-0963

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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