HGNC Approved Gene Symbol: SNAP29
SNOMEDCT: 722385008;
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:20,859,007-20,891,214 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
22q11.21 | Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome | 609528 | Autosomal recessive | 3 |
Intracellular membrane traffic appears to be regulated in part by SNAREs, SNAP (soluble N-ethylmaleimide-sensitive factor-attachment protein; see SNAP-alpha, 603215) receptors, through the formation of complexes between SNAREs on vesicle and target membranes. In the nerve terminal, the core fusion complex is a parallel bundle of 4 helices formed from the coiled-coil domains of 3 proteins. Two helices are contributed by the SNAP25 (600322) plasma membrane protein, and 1 helix each comes from a vesicle SNARE, or VAMP, and a target membrane SNARE, or syntaxin. Dissociation of the core complex is mediated by recruitment of the NSF (601633) ATPase chaperone and SNAP-alpha to the complex, followed by ATP hydrolysis, thereby allowing the components to recycle for another round of membrane fusion (summary by Steegmaier et al., 1998).
By carrying out a yeast 2-hybrid screen with syntaxin-3 (600876) as bait, Steegmaier et al. (1998) isolated a partial cDNA encoding a protein with homology to SNAP25 and SNAP23 (602534). They used the partial cDNA to screen a brain library and recovered a cDNA corresponding to the complete coding sequence of the gene, which they called SNAP29 based on the predicted molecular weight of the encoded product. The deduced 258-amino acid SNAP29 protein is 17% identical to SNAP25 and SNAP23. Like SNAP23 and SNAP25, SNAP29 contains 2 predicted coiled-coil regions that can participate in the formation of the core complex. However, SNAP29 lacks the palmitoylated membrane-attachment domain found in the other 2 proteins and has a distinct localization pattern. Immunofluorescence studies of epitope-tagged SNAP29 indicated that it localized predominantly to intracellular membrane structures, whereas SNAP25 and SNAP23 are primarily localized to the plasma membrane. Northern blot analysis revealed that SNAP29 is expressed ubiquitously as a major 1.4-kb mRNA and 3 less abundant transcripts.
By in situ hybridization, Keser et al. (2019) showed that Snap29 was ubiquitously expressed during mouse embryogenesis.
Gross (2013) mapped the SNAP29 gene to chromosome 22q11.21 based on an alignment of the SNAP29 sequence (GenBank AF115436) with the genomic sequence (GRCh37).
Steegmaier et al. (1998) found that in vitro SNAP29 bound to a broader range of syntaxin fusion proteins than did SNAP25 or SNAP23. Steegmaier et al. (1998) proposed that SNAP29 is bound to membrane structures via its interaction with multiple syntaxins, and that it is capable of participating in various intracellular transport steps, interacting with different syntaxins and VAMPs specifically localized to distinct membrane compartments.
Through several in vitro and in vivo binding assays, Hohenstein and Roche (2001) confirmed that SNAP29 binds to plasma membrane syntaxins as well as to syntaxins present on many different internal membranes. By coimmunoprecipitation studies, they also found that the association between syntaxin-6 and SNAP29 is enhanced in cells coexpressing VAMP. Rotem-Yehudar et al. (2001) found evidence for a role of SNAP29 in the endocytosis of IGF1 receptors (IGF1R; 147370). They found that EHD1 (605888) and SNAP29 interact directly with each other and are present in complexes with IGF1R. Following IGF1 induction, EHD1 and IGF1R colocalize intracellularly. Immunoprecipitation of rat tissues also suggested interaction of SNAP29 with AP2A1 (601026).
In 7 members of an Arab family with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK; 609528), Sprecher et al. (2005) identified a homozygous mutation in the SNAP29 gene (604202.0001).
In a Pakistani brother and sister with CEDNIK syndrome, Fuchs-Telem et al. (2011) identified homozygosity for a 1-bp insertion in the SNAP29 gene (604202.0002).
In 2 sisters, born to consanguineous Jordanian parents, with CEDNIK syndrome, Ben-Salem et al. (2015) identified homozygosity for the same c.220delG mutation in the SNAP29 that had previously been identified in affected members of an Arab family by Sprecher et al. (2005), suggesting a founder mutation.
In a 12-year-old boy of Caucasian/Hispanic descent with a variant of CEDNIK, Llaci et al. (2019) identified compound heterozygous mutations in the SNAP29 gene (604202.0003 and 604202.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. SNAP29 expression was significantly lower in the patient's blood cells compared to controls. Western blot analysis of patient fibroblasts showed an absence of the full-length protein. These findings were consistent with a loss of function, although additional functional studies were not performed. The patient had congenital nystagmus, hypotonia, delayed development, mild optic atrophy, and hypomyelinating leukodystrophy. He did not have cerebral dysgenesis, ichthyosis, keratoderma, or neuropathy, thus expanding the phenotypic spectrum associated with biallelic SNAP29 mutations.
In 5 patients from 4 unrelated families with CEDNIK, Mah-Som et al. (2021) identified homozygous putative loss-of-function mutations in the SNAP29 gene (see, e.g., 604202.0003-604202.0005). The mutations, which were found by various genetic sequencing techniques, segregated with the disorder in the families. There were 2 frameshift and 1 nonsense mutations, as well as a mutation that interrupted the initiation codon. Functional studies of the variants and studies of patient cells were not performed.
In 2 sisters, born of consanguineous Syrian parents, with CEDNIK, Nanda et al. (2022) identified a homozygous frameshift mutation in the SNAP29 gene (604202.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Keser et al. (2019) found that Snap29 -/- mice were born at the expected mendelian ratio and mostly survived to adulthood. A small fraction of Snap29 -/- pups, with no apparent defects, died within 2 days of birth. Snap29 -/- pups that survived the perinatal period developed diverse skin defects, including epidermal hyperkeratosis, recapitulating the variable expressivity and penetrance of skin abnormalities found in CEDNIK patients. Although skin barrier formation was delayed in Snap29 -/- embryos, a functional skin barrier was present at birth. Snap29 -/- mice also had skeletal abnormalities and dysmorphisms found in patients with SNAP29 mutations, but these phenotypes showed incomplete penetrance and variable expressivity. Moreover, Snap29 -/- mice had motor defects, moved slower than controls, and showed preferential use of forelimbs for movement. Gait defects were due to changes in strength, as Snap29 -/- mice presented with reduced grip strength, first in their hindlimbs, and later in both hindlimbs and forelimbs as they aged, phenocopying hypotonia found in CEDNIK patients. Furthermore, Snap29 -/- mice exhibited retinal defects, like the ophthalmologic abnormalities found in CEDNIK, although with reduced penetrance. Additionally, Snap29 -/- males were infertile, as Snap29 was required for spermatogenesis and male fertility.
In affected patients with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK; 609528), Sprecher et al. (2005) identified a 1-bp deletion (220delG) in the SNAP29 gene, resulting in premature termination of the protein. The mutation was not identified in 200 control chromosomes. RT-PCR showed significantly reduced SNAP29 expression in the skin of affected individuals. Sprecher et al. (2005) concluded that SNAP29 is essential for proper vesicle trafficking in neuroectodermal differentiation.
Mah-Som et al. (2021) noted that Sprecher et al. (2005) referred to this mutation as 220delG because they started numbering after the initiation codon, and referred to this mutation as c.223delG.
In 2 sisters, born to consanguineous Jordanian parents, with CEDNIK syndrome, Ben-Salem et al. (2015) identified homozygosity for the c.220delG mutation in the SNAP29 gene, suggesting a founder mutation.
In 2 sisters, born of consanguineous Syrian parents, with CEDNIK, Nanda et al. (2022) identified a homozygous 1-bp deletion (c.223delG) in the SNAP29 gene, predicted to result in a frameshift and premature termination (Val75SerfsTer28). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In a Pakistani brother and sister with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK; 609528), Fuchs-Telem et al. (2011) identified homozygosity for a 1-bp insertion (c.486insA) in the SNAP29 gene, causing a frameshift predicted to result in premature termination. The mutation was not found in 200 control chromosomes; DNA from other family members was not available. Premature termination was confirmed by Western blot analysis, and transfection studies in HeLa cells demonstrated complete loss of the wildtype distribution pattern with the mutant construct. In addition, histologic features typical for CEDNIK syndrome were replicated in 3-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29.
In Pakistani patients with cortical dysplasia originally reported by Abdollahi et al. (2009), Diggle et al. (2017) identified a homozygous 1-bp duplication (c.487dupA) in the SNAP29 gene, resulting in a frameshift and premature termination (Ser163LysfsTer6). Abdollahi et al. (2009) had identified a homozygous variation in the TUBA8 gene (see 605742.0001) in these patients. However, Diggle et al. (2017) concluded that the phenotype in these patients was likely due to the SNAP29 mutation. Functional studies of the SNAP29 mutation were not performed.
In 2 sibs (P1 and P2), born of consanguineous Amish/Mennonite parents, with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK; 609528), Mah-Som et al. (2021) identified a homozygous c.2T-C transition in the SNAP29 gene, predicted to alter the initiation codon. The mutation segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. P1 was a 19-year-old woman, illustrating the longest known survival of CEDNIK patients.
In a 12-year-old boy of Caucasian/Hispanic descent with a variant of CEDNIK, Llaci et al. (2019) identified compound heterozygous mutations in the SNAP29 gene: c.2T-C and c.354dupG, resulting in a frameshift (604202.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. SNAP29 expression was significantly lower in the patient's blood cells compared to controls. Western blot analysis of patient fibroblasts showed an absence of the full-length protein, suggesting that the frameshift mutation results in nonsense-mediated mRNA decay. These findings were consistent with a loss of function, although additional functional studies were not performed. The patient had congenital nystagmus, hypotonia, delayed development, mild optic atrophy, and hypomyelinating leukodystrophy. He did not have cerebral dysgenesis, ichthyosis, keratoderma, or neuropathy, thus expanding the phenotypic spectrum associated with biallelic SNAP29 mutations.
In a 9-year-old girl (P3), born of consanguineous parents of Hispanic Mexican descent, with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK; 609528), Mah-Som et al. (2021) identified a homozygous 1-bp duplication (c.354dupG) in the SNAP29 gene, predicted to result in a frameshift and premature termination (Leu119AlafsTer15). The mutation segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
For discussion of the 1-bp duplication (c.354dupG, NM_004782.3) in the SNAP29 gene that was found in compound heterozygous state in a patient with a variant of CEDNIK by Llaci et al. (2019), see 604202.0003.
In a 4-year-old girl (P4), born of unrelated parents of Tibetan and Indian descent, with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK; 609528), Mah-Som et al. (2021) identified a homozygous c.622G-T transversion in the SNAP29 gene, resulting in a glu208-to-ter (E208X) substitution. The mutation segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Abdollahi, M. R., Morrison, E., Sirey, T., Molnar, Z., Hayward, B. E., Carr, I. M., Springell, K., Woods, C. G., Ahmed, M., Hattingh, L., Corry, P., Pilz, D. T., Stoodley, N., Crow, Y., Taylor, G. R., Bonthron, D. T., Sheridan, E. Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia. Am. J. Hum. Genet. 85: 737-744, 2009. [PubMed: 19896110] [Full Text: https://doi.org/10.1016/j.ajhg.2009.10.007]
Ben-Salem, S., Sobreira, N., Al-Shamsi, A. M., Valle, D., Ali, B. R., Al-gazali, L. New Arab family with cerebral dysgenesis, neuropathy, ichthyosis and keratoderma syndrome suggests a possible founder effect for the c.223delG mutation. (Letter) J. Derm. 42: 821-822, 2015. [PubMed: 25958742] [Full Text: https://doi.org/10.1111/1346-8138.12917]
Diggle, C. P., Martinez-Garay, I., Molnar, Z., Brinkworth, M. H., White, E., Fowler, E., Hughes, R., Hayward, B. E., Carr, I. M., Watson, C. M., Crinnion, L., Asipu, A., Woodman, B., Coletta, P. L., Markham, A. F., Dear, T. N., Bonthron, D. T., Peckham, M., Morrison, E. E., Sheridan, E. A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development. PLoS One 12: e0174264, 2017. Note: Electronic Article. [PubMed: 28388629] [Full Text: https://doi.org/10.1371/journal.pone.0174264]
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. I., Horowitz, M., Sprecher, E. CEDNIK syndrome results from loss-of-function mutations in SNAP29. Brit. J. Derm. 164: 610-616, 2011. [PubMed: 21073448] [Full Text: https://doi.org/10.1111/j.1365-2133.2010.10133.x]
Gross, M. B. Personal Communication. Baltimore, Md. 5/9/2013.
Hohenstein, A. C., Roche, P. A. SNAP-29 is a promiscuous syntaxin-binding SNARE. Biochem. Biophys. Res. Commun. 285: 167-171, 2001. [PubMed: 11444821] [Full Text: https://doi.org/10.1006/bbrc.2001.5141]
Keser, V., Lachance, J.-F. B., Alam, S. S., Lim, Y., Scarlata, E., Kaur, A., Zhang, T. F., Lv, S., Lachapelle, P., O'Flaherty, C., Golden, J. A., Jerome-Majewska, L. A. Snap29 mutant mice recapitulate neurological and ophthalmological abnormalities associated with 22q11 and CEDNIK syndrome. Commun. Biol. 2: 375, 2019. [PubMed: 31633066] [Full Text: https://doi.org/10.1038/s42003-019-0601-5]
Llaci, L., Ramsey, K., Belnap, N., Claasen, A. M., Balak, C. D., Szelinger, S., Jepsen, W. M., Siniard, A. L., Richholt, R., Izat, T., Naymik, M., De Both, M., Piras, I. S., Craig, D. W., Huentelman, M. J., Narayanan, V., Schrauwen, I., Rangasamy, S. Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD). Hum. Genet. 138: 1409-1417, 2019. [PubMed: 31748968] [Full Text: https://doi.org/10.1007/s00439-019-02077-7]
Mah-Som, A. Y., Skrypnyk, C., Guerin, A., Seroor Jadah, R. H., Vardhan, V. N., McKinstry, R. C., Shinawi, M. S. New cohort of patients with CEDNIK syndrome expands the phenotypic and genotypic spectra. Neurol. Genet. 7: e553, 2021. [PubMed: 33977139] [Full Text: https://doi.org/10.1212/NXG.0000000000000553]
Nanda, A., Karam, T. M., AlLafi, A. CEDNIK syndrome with phenotypic variability. Pediat. Derm. 39: 650-652, 2022. [PubMed: 35229899] [Full Text: https://doi.org/10.1111/pde.14961]
Rotem-Yehudar, R., Galperin, E., Horowitz, M. Association of insulin-like growth factor 1 receptor with EHD1 and SNAP29. J. Biol. Chem. 276: 33054-33060, 2001. [PubMed: 11423532] [Full Text: https://doi.org/10.1074/jbc.M009913200]
Sprecher, E., Ishida-Yamamoto, A., Mizrahi-Koren, M., Rapaport, D., Goldsher, D., Indelman, M., Topaz, O., Chefetz, I., Keren, H., O'Brien, T. J., Bercovich, D., Shalev, S., Geiger, D., Bergman, R., Horowitz, M., Mandel, H. 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. Am. J. Hum. Genet. 77: 242-251, 2005. [PubMed: 15968592] [Full Text: https://doi.org/10.1086/432556]
Steegmaier, M., Yang, B., Yoo, J.-S., Huang, B., Shen, M., Yu, S., Luo, Y., Scheller, R. H. Three novel proteins of the syntaxin/SNAP-25 family. J. Biol. Chem. 273: 34171-34179, 1998. [PubMed: 9852078] [Full Text: https://doi.org/10.1074/jbc.273.51.34171]