The SEC23A gene is mapped to chromosome 14q21.1. The gene encodes a member of the SEC23 subfamily of the SEC23/SEC24 family. The SEC23A protein is found in the ribosomal-free transitional face of the endoplasmic reticulum (ER) and associated vesicles. The encoded protein plays an important role in the ER-Golgi protein trafficking by promoting the transport of secretory, plasma membrane, and vacuolar proteins from the endoplasmic reticulum to the Golgi complex. Mutation of the SEC23A gene causes Cranio-Lenticular-Sutural Dysplasia (CLSD), a novel autosomal recessive disorder.
The SEC23A gene comprises 19 coding exons, and spans approximately 77.7 kb in the genomic DNA. The encoded protein consists of 765 amino acids, and weighs 86.161 kDa. Mutations in this gene have been identified in patients with craniolenticulosutural dysplasia.
Boyadjiev et al. (2003) performed a genome-wide scan in a Saudi family of Bedouin descent with 21 members including five males and one female diagnosed with craniolenticulosutural dysplasia. All affected members were homozygous for a 7.26 Mb region between markers D14S1014 and D14S306 on chromosome 14q13-q21. Boyadjiev et al. (2003) performed sequence analysis of the PAX9 gene, but found no mutations. In a subsequent study, Boyadjiev et al. (2006) analyzed 47 genes in the candidate chromosomal region by direct sequencing of cDNA. A homozygous missense 1144T>C transition (p.F382L) in exon 10 of the SEC23A gene was observed in all affected patients. The mutation, which involved a residue that is invariably conserved in at least 10 species, was not present in 600 control chromosomes. The mutation results in defective COPII-mediated endoplasmic reticulum export of the secretory proteins required for normal morphogenesis accounts for CLSD. Liposome-binding assays and cell-free vesicle budding assays showed that SEC23A with the p.F382L substitution could bind SAR1B and SEC24D and could bind membranes, but it was defective in its function in vesicle budding. Boyadjiev et al. (2006) suggested that disrupted endoplasmic reticulum export of secretory proteins required for normal morphogenesis accounts for CLSD. At a much later time, Boyadjiev et al. (2011) reported a 4.5-year-old boy with facial features characteristic of CLSD, but had different eye phenotypes. They identified heterozygosity for a paternally inherited missense mutation transition in the SEC23A gene (c.2104A>G) resulting in a p.M702V substitution at a residue that is invariably conserved in all higher eukaryotes. The M702V mutation was not present in 372 Caucasian control chromosomes. No mutations were identified in the coding region or 5-prime or 3-prime UTR of maternal SEC23A, and SNP and RT-PCR analysis excluded deletion of the maternal allele. RT-PCR DNA sequencing of the SEC23B, SEC31A, and SEC13 genes revealed no mutations. Cultured skin fibroblasts from the patient showed a severe secretion defect of collagen with enlarged endoplasmic reticulum (ER); milder collagen secretion defects and ER distention were present in fibroblasts from the clinically unaffected father, indicating that an additional mutation was present in the proband. This observation prompted Boyadjiev et al. (2011) to suggest that digenic inheritance might be involved in CLSD.