Alternative titles; symbols
HGNC Approved Gene Symbol: STX16
Cytogenetic location: 20q13.32 Genomic coordinates (GRCh38) : 20:58,651,283-58,679,526 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.32 | Pseudohypoparathyroidism Ib | 603233 | Autosomal dominant | 3 |
SNAREs (SNAP receptors) are molecules involved in synaptic vesicle docking and fusion. V-SNAREs, found on vesicles, interact with t-SNAREs (syntaxins), found on target membranes, in a specific manner. See alpha-SNAP (603215). By searching sequence databases for syntaxin-like proteins, Tang et al. (1998) identified a human cDNA encoding a novel syntaxin, which they designated syntaxin-16 (SYN16). The predicted 307-amino acid protein contains the C-terminal hydrophobic tail anchor characteristic of syntaxins, and several potential coiled-coil regions. Using immunofluorescence, the authors determined that an epitope-tagged SYN16 protein localized to the Golgi apparatus. Northern blot analysis revealed that the 6.5-kb SYN16 mRNA is expressed ubiquitously. Independently, Simonsen et al. (1998) isolated cDNAs encoding 3 isoforms of syntaxin-16, syntaxin-16A, -16B, and -16C. The 16C isoform is truncated, lacks the hydrophobic and coiled-coil regions, and localizes to the cytoplasm. The authors found that the 16A isoform associates posttranslationally with microsomes, and appears to be transported to the Golgi via the endoplasmic reticulum.
Bastepe et al. (2003) mapped the STX16 gene to chromosome 20q13.3 by genomic sequence analysis.
In affected members and obligate carriers from 12 unrelated families with pseudohypoparathyroidism Ib (603233), Bastepe et al. (2003) identified a 3-kb heterozygous microdeletion located approximately 220 kb centromeric of exon 1A of the GNAS gene (139320), which was postulated to disrupt imprinting. Four of 16 apparently sporadic patients also had the deletion. In all examined cases, the deletion was inherited from the mother, consistent with the observation of PHP Ib developing only in offspring of female obligate carriers. The deletion removed 3 of 8 exons encoding syntaxin-16 (603666.0001). Bastepe et al. (2003) postulated that the microdeletion disrupts a putative cis-acting element required for methylation at exon 1A and that this genetic defect underlies the pathogenesis of PHP Ib.
Linglart et al. (2005) reported a novel heterozygous 4.4-kb microdeletion in a large kindred with autosomal dominant PHP Ib. Affected individuals from this kindred shared an epigenetic defect that was indistinguishable from that observed in patients with the same clinical disorder who carried the 3-kb microdeletion in the STX16 region (Bastepe et al., 2003), i.e., an isolated loss of methylation at GNAS exon A/B. The novel 4.4-kb microdeletion overlapped with a region of the 3-kb microdeletion and, similar to the latter deletion, removed several exons of STX16. Because these microdeletions led to AD-PHP Ib only after maternal transmission, Linglart et al. (2005) analyzed expression of STX16 in lymphoblastoid cells of affected individuals with the 3-kb or the 4.4-kb microdeletion, an individual with a NESP55 deletion, and a healthy control. They found that STX16 mRNA was expressed in all cases from both parental alleles. Thus, STX16 is apparently not imprinted, and a loss-of-function mutation in 1 allele is unlikely to be responsible for this disorder. Instead, the region of overlap between the 2 microdeletions likely harbors a cis-acting imprinting control element that is necessary for establishing and/or maintaining methylation at GNAS exon A/B, thus allowing normal expression of Gs-alpha expression in the proximal renal tubules. In the presence of either of the 2 microdeletions, parathyroid hormone resistance appears to develop over time, as documented in an affected individual who was diagnosed at birth with a 4.4-kb deletion of STX16 but had normal serum parathyroid hormone levels until the age of 21 months.
In affected members and obligate carriers of 12 unrelated families with pseudohypoparathyroidism type Ib (603233), Bastepe et al. (2003) identified a 3-kb heterozygous microdeletion located approximately 220 kb centromeric of exon 1A, which they called exon A/B, of the GNAS gene (see also 139320.0031). Four of 16 apparently sporadic patients also had the deletion. Affected individuals with the microdeletion showed loss of exon 1A methylation, but no other epigenetic abnormalities. In all examined cases, the deletion was inherited from the mother, consistent with the observation of PHP Ib developing only in offspring of female obligate carriers. The deletion removed 3 of 8 exons encoding STX16, but Bastepe et al. (2003) considered the involvement of STX16 in the molecular pathogenesis of PHP Ib unlikely. They postulated that the microdeletion disrupts a putative cis-acting control element required for methylation at exon 1A and that this epigenetic defect underlies the pathogenesis of PHP Ib.
Laspa et al. (2004) reported a Greek PHP Ib kindred with 4 affected members and 3 obligate carriers who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. Affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.
In all affected individuals and obligate carriers in a large kindred with PHP Ib, Linglart et al. (2005) identified a 4.4-kb microdeletion overlapping with a region of the 3-kb deletion identified by Bastepe et al. (2003). The 4.4-kb deletion removed exons 2-4 of the STX16 gene, whereas the 3-kb deletion removed exons 4-6. Both microdeletions lead to PHP Ib only after maternal transmission, and affected individuals exhibit loss of methylation only at GNAS exon A/B. Linglart et al. (2005) determined that the STX16 gene is not imprinted, and proposed that the region of overlap between the microdeletions contains a cis-acting imprinting control element that is necessary for establishing and/or maintaining methylation at GNAS exon A/B.
Bastepe, M., Frohlich, L. F., Hendy, G. N., Indridason, O. S., Josse, R. G., Koshiyama, H., Korkko, J., Nakamoto, J. M., Rosenbloom, A. L., Slyper, A. H., Sugimoto, T., Tsatsoulis, A., Crawford, J. D., Juppner, H. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J. Clin. Invest. 112: 1255-1263, 2003. [PubMed: 14561710] [Full Text: https://doi.org/10.1172/JCI19159]
Laspa, E., Bastepe, M., Juppner, H., Tsatsoulis, A. Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance. J. Clin. Endocr. Metab. 89: 5942-5947, 2004. [PubMed: 15579741] [Full Text: https://doi.org/10.1210/jc.2004-0249]
Linglart, A., Gensure, R. C., Olney, R. C., Juppner, H., Bastepe, M. A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am. J. Hum. Genet. 76: 804-814, 2005. Note: Erratum: Am. J. Hum. Genet. 81: 196 only, 2007. [PubMed: 15800843] [Full Text: https://doi.org/10.1086/429932]
Simonsen, A., Bremnes, B., Ronning, E., Aasland, R., Stenmark, H. Syntaxin-16, a putative Golgi t-SNARE. Europ. J. Cell Biol. 75: 223-231, 1998. [PubMed: 9587053] [Full Text: https://doi.org/10.1016/S0171-9335(98)80116-7]
Tang, B. L., Low, D. Y. H., Lee, S. S., Tan, A. E. H., Hong, W. Molecular cloning and localization of human syntaxin 16, a member of the syntaxin family of SNARE proteins. Biochem. Biophys. Res. Commun. 242: 673-679, 1998. [PubMed: 9464276] [Full Text: https://doi.org/10.1006/bbrc.1997.8029]