A Mutation in SNAP29, Coding for a SNARE Protein Involved in Intracellular Trafficking, Causes a Novel Neurocutaneous Syndrome Characterized by Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Palmoplantar Keratoderma

Abstract

Neurocutaneous syndromes represent a vast, largely heterogeneous group of disorders characterized by neurological and dermatological manifestations, reflecting the common embryonic origin of epidermal and neural tissues. In the present report, we describe a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK syndrome). Using homozygosity mapping in two large families, we localized the disease gene to 22q11.2 and identified, in all patients, a 1-bp deletion in SNAP29, which codes for a SNARE protein involved in vesicle fusion. SNAP29 expression was decreased in the skin of the patients, resulting in abnormal maturation of lamellar granules and, as a consequence, in mislocation of epidermal lipids and proteases. These data underscore the importance of vesicle trafficking regulatory mechanisms for proper neuroectodermal differentiation.

Inherited ichthyoses/generalized Mendelian disorders of cornification

“…42,43 Immunohistochemical staining confirms FLG deficiency in IV (Figures 1l and m) 44 and reveals absent or reduced expression of lympho-epithelial kazal-type-related inhibitor and SNAP29 in NS and CEDNIK, respectively. [45][46][47] In addition, light microscopy of hair shafts demonstrates 'bamboo hairs' (trichorrhexis invaginata) in NS (Figure 1j) 48 and polarization microscopy of TTD patient hairs reveals a tiger-tail pattern that corresponds to the diagnostic low sulfur protein content (Figure 1i). 49,50 Electron microscopy.…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…92,93 Recent studies on genotype-phenotype correlation distinguish the TTD syndromes associated with ichthyosis of delayed onset or accompanied with collodion membrane from other forms of TTD. 94 Diseases relatively new in the list of ichthyoses are loricrin keratoderma, also referred to as Camisa variant of Vohwinkel keratoderma (Fig 4, C ), [95][96][97] the cerebral dysgenesiseneuropathyeichthyosisePPK syndrome, 98 the arthrogryposiserenal dysfunctionecholestasis syndrome, 99-101 the mental retardationeenteropathye deafnesseneuropathyeichthyosisekeratodermia syndrome, 102 the ichthyosisehypotrichosisesclerosing cholangitis syndrome (also known as neonatal ichthyosis sclerosing cholangitis syndrome), 103-105 the ichthyosis hypotrichosis syndrome (Fig 5, I ) 106 and its allelic variant congenital ichthyosisefollicular atrophodermaehypotrichosisehypohidrosis syndrome, 107,108 and keratosis lineariseichthyosisecongenital sclerosing keratoderma (Fig 4, F ). 109,110 Erythrokeratodermia variabilis (EKV), [111][112][113] which is characterized by migratory erythematous patches and more fixed, symmetric hyperkeratotic plaques often with palmoplantar involvement (Fig 4, B), is genetically heterogeneous and can in 50% to 65% of cases 114 be caused by mutations in GJB3 coding for the gap junction protein connexin 31, 115 or GJB4 coding for connexin 30.3.…”

Thematic review series: Skin Lipids. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

“…Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome A noncongenital neurocutaneous syndrome with microcephaly, mental retardation, generalized ichthyosis, and palmoplantar keratoderma was recently ascribed to mutations in the SNAP29 gene, encoding for the SNARE29 protein involved in intracellular vesicle fusion (210). Aside from normal-appearing LBs, the epidermis of these patients exhibits numerous vesicular structures of varying size in the SG and SC layers that contain glucosylceramide, KLK5, and KLK7 (210).…”