Alternative titles; symbols
HGNC Approved Gene Symbol: STT3A
Cytogenetic location: 11q24.2 Genomic coordinates (GRCh38): 11:125,591,769-125,623,091 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q24.2 | Congenital disorder of glycosylation, type Iw, autosomal dominant | 619714 | Autosomal dominant | 3 |
| Congenital disorder of glycosylation, type Iw, autosomal recessive | 615596 | Autosomal recessive | 3 |
The STT3A gene encodes a catalytic subunit of the oligosaccharide (OST) protein complex that carries out glycan chain transfer to proteins in the endoplasmic reticulum. The STT3 proteins (see also STT3B, 608605) specifically transfer oligosaccharides onto asparagine residues. STT3A and STT3B exist in different OST complexes with different kinetic properties and substrate preferences, but they have overlapping roles (summary by Shrimal et al., 2013).
From a fetal mouse mandibular condyle cDNA library, Hong et al. (1996) isolated a novel cDNA coding for a highly hydrophobic protein that the authors called B5. The full-length mouse B5 cDNA was 3,095 nucleotides long and contained a potential open reading frame coding for a protein of 705 amino acids with a calculated molecular mass of 80.5 kD. The B5 mRNA was differentially polyadenylated, with the most abundant transcript having a length of 2.7 kb. Hong et al. (1996) isolated the human homolog of B5 from a cDNA testis library. The amino acid sequence of the human B5 was 98.5% identical to that of the mouse protein. A striking feature of the B5 protein was the presence of numerous (10 to 14) potential transmembrane domains, characteristic of an integral membrane protein. Similarity searches in public databases revealed that B5 is 58% similar to the T12A2.2 gene of C. elegans and 60% similar to the Stt3 gene of S. cerevisiae. A human EST related to human B5 and identical to the Stt3 gene indicated to Hong et al. (1996) that B5 belongs to a larger gene family coding for novel putative transmembrane proteins. They observed that this family exhibits a remarkable degree of conservation across species.
Lissy et al. (1996) used differential display PCR to identify genes expressed at higher levels in malignant mesotheliomas than in normal mesothelial cells. They isolated and cloned from a human fetal brain library a full-length ITM1 cDNA, which they termed TMC. The predicted 705-amino acid protein has 13 putative transmembrane domains. Northern blot analysis revealed that the gene is expressed in a variety of human tissues, with highest expression in ovary and testis. Northern blot and RT-PCR analysis showed no differences in the level of expression among normal and malignant mesothelial cell lines tested.
By linkage analysis, Hong et al. (1996) mapped the mouse B5 gene, which they symbolized Itm1 (for integral membrane protein-1) to chromosome 9. Based on human/mouse homology and preliminary findings in a panel of rodent/human somatic cell hybrids, the human ITM1 gene is likely to map to 11q23-q24.
Van Hul et al. (1996) mapped the ITM1 gene to 11q23.3 by fluorescence in situ hybridization (FISH) and by PCR screening of a chromosome 11-specific YAC library. By FISH, Lissy et al. (1996) mapped the ITM1 gene to human chromosome 11q24-q25.
Dumax-Vorzet et al. (2013) found that human OST4 (618932) assembled into distinct OST complexes through association with STT3A or STT3B, as well as with the OST accessory subunit, ribophorin I (RPN1; 180470). Knockdown experiments showed that OST4 preferentially stabilized STT3A and its interacting partner, KCP2 (KRTCAP2; 619029). STT3A and/or ribophorin I, in turn, stabilized OST4 in the complex. Depletion of OST4 destabilized both STT3A- and STT3B-containing OST complexes and released a ribophorin I-containing subcomplex. OST4 and ribophorin I stabilized whole OST complexes, and both proteins modulated the efficiency of N-glycosylation of endogenous prosaposin (PSAP; 176801) in HeLa cells.
By substrate screening in HEK293T cells, Knopf et al. (2020) identified OST complex subunits, including STT3A, as RHBDL4 (617515) substrates. RHBDL4 was required for OST complex homeostasis, as cleavage by RHBDL4 led to dislocation of substrates into the cytoplasm and subsequent degradation by the proteasome. RHBDL4 cleaved STT3A at 2 distinct luminal loops, facilitated by a negatively charged transmembrane segment of RHBDL4 assisting substrate recruitment. Knockout analysis in HEK293T cells demonstrated that, by cleaving functional OST complexes, RHBDL4 modulated the ER glycosylation capacity of cells.
Congenital Disorder of Glycosylation, Type Iw, Autosomal Recessive
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive congenital disorder of glycosylation type Iw (CDG1WAR; 615596), Shrimal et al. (2013) identified a homozygous missense mutation in the STT3A gene (V626A; 601134.0001). The mutation was found by homozygosity mapping and candidate gene sequencing. At age 13 years, both patients showed developmental delay, failure to thrive, seizures, and hypotonia. One was more severely affected, with an inability to sit, weak visual tracking, and intractable seizures. Serum transferrin analysis showed an abnormal type I pattern of glycosylation. Patient cells showed reduced amounts of the STT3A protein. Patient cells also showed incomplete N-glycosylation of a GFP biomarker that was complemented by wildtype STT3A, as well as lower glycosylation of the STT3A substrates prosaposin (PSAP; 176801) and granulin (GRN; 138945) compared to control cells.
Ghosh et al. (2017) identified homozygosity for the V626A mutation in the STT3A gene in 5 individuals from a multiply consanguineous Pakistani family with CDG1WAR. The mutation was found by autozygosity mapping and whole-exome sequencing and was confirmed by Sanger sequencing. Two of those affected were also homozygous (patient IV-1) or heterozygous (patient IV-2) for a partial deletion of the TUSC3 gene (601385); patient IV-1 had a more severe neurodevelopmental clinical course compared to other affected family members, whereas patient IV-2 had a similar phenotype to family members with only the STT3A mutation.
Congenital Disorder of Glycosylation, Type Iw, Autosomal Dominant
In 16 patients from 9 families with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygous missense mutations in the STT3A gene (601134.0002-601134.0008). The mutations were identified by whole-exome or whole-genome sequencing. The 7 mutations were located around the protein catalytic site. Transfection of S. cerevisiae with STT3A with each of the corresponding mutations demonstrated a dominant-negative effect and hypoglycosylation of the carboxypeptidase Y protein. Wilson et al. (2021) concluded that because STT3A is the catalytic subunit of the oligosaccharyltransferase complex, mutations disrupting the catalytic subunit likely disrupt transfer of N-glycans onto glycoproteins.
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive congenital disorder of glycosylation type Iw (CDG1WAR; 615596), Shrimal et al. (2013) identified a homozygous c.1877T-C transition in the STT3A gene, resulting in a val626-to-ala (V626A) substitution. The mutation was found by homozygosity mapping and candidate gene sequencing. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 1,110 Middle Eastern control exomes. At age 13 years, both patients showed developmental delay, failure to thrive, seizures, and hypotonia. One patient was more severely affected, with an inability to sit, weak visual tracking, and intractable seizures. Serum transferrin analysis showed an abnormal type I pattern of glycosylation. Patient cells showed reduced amounts of the STT3A protein. Patient cells also showed incomplete N-glycosylation of a GFP biomarker that was complemented by wildtype STT3A, as well as lower glycosylation of the STT3A substrates prosaposin (PSAP; 176801) and granulin (GRN; 138945) compared to control cells.
Ghosh et al. (2017) identified homozygosity for the V626A mutation in the STT3A gene in 5 individuals from a multiply consanguineous Pakistani family with CDG1WAR. The mutation was found by autozygosity mapping and whole-exome sequencing and was confirmed by Sanger sequencing. Two of those affected were also homozygous (patient IV-1) or heterozygous (patient IV-2) for a partial deletion of the TUSC3 gene (601385); patient IV-1 had a more severe neurodevelopmental clinical course compared to other affected family members, whereas patient IV-2 had a similar phenotype to family members with only the STT3A mutation.
In a mother and her 2 sons (family 1) with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygosity for a c.1637C-T transition (c.1637C-T, NM_001278503.1) in the STT3A gene, resulting in a thr546-to-ile (T546I) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with disorder in the family. The mutation is located around the STT3A catalytic site. A type 1 transferrin glycosylation profile was detected in all 3 family members. S. cerevisiae cells transfected with the corresponding yeast Stt3 mutation (T537I) demonstrated protein (carboxypeptidase A) hypoglycosylation.
In a father and daughter (family 2) with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygosity for a c.1589A-C transversion (c.1589A-C, NM_001278503.1) in the STT3A gene, resulting in a tyr530-to-ser (Y530S) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with disorder in the family. The mutation is located around the STT3A catalytic site. A type 1 transferrin glycosylation profile was detected both family members. S. cerevisiae cells transfected with the corresponding yeast Stt3 mutation (Y521S) demonstrated protein (carboxypeptidase A) hypoglycosylation.
In a 15-year-old girl (family 3) with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygosity for a c.137A-G transition (c.137A-G, NM_001278503.1) in the STT3A gene, resulting in a his46-to-arg (H46R) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, occurred de novo. The mutation is located around the STT3A catalytic site. A type 1 transferrin glycosylation profile was detected in the patient. S. cerevisiae cells transfected with the corresponding yeast Stt3 mutation (H44R) demonstrated protein (carboxypeptidase A) hypoglycosylation.
In a 24-year-old man (family 4) with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygosity for a c.479G-A transition (c.479G-A, NM_001278503.1) in the STT3A gene, resulting in an arg160-to-gln (R160Q) substitution. The mutation, which was identified by next-generation sequencing and confirmed by Sanger sequencing, was occurred de novo. The mutation is located around the STT3A catalytic site. A type 1 transferrin glycosylation profile was detected in the patient. S. cerevisiae cells transfected with the corresponding yeast Stt3 mutation (R159Q) demonstrated protein (carboxypeptidase A) hypoglycosylation.
In 3 patients from 3 unrelated families (families 5, 6, 7) with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygosity for a c.1213C-T transition (c.1213C-T, NM_001278503.1) in the STT3A gene, resulting in an arg405-to-cys (R405C) substitution. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing. The mutation occurred de novo in family 6; DNA was not available from one of the parents in the other families. The mutation is located around the STT3A catalytic site. A type 1 transferrin glycosylation profile was detected in the patients. S. cerevisiae cells transfected with the corresponding yeast Stt3 mutation (R404C) demonstrated protein (carboxypeptidase A) hypoglycosylation.
In a father and his 3 children (family 8) with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygosity for a c.1214G-A transition (c.1214G-A, NM_001278503.1) in the STT3A gene, resulting in an arg405-to-his (R405H) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was identified in the gnomAD database with an allele frequency of 2 in 292,294. A type 1 transferrin glycosylation profile was detected in all 4 family members.
In a mother and son (family 9) with autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD; 619714), Wilson et al. (2021) identified heterozygosity for a c.985C-T transition (c.985C-T, NM_001278503.1) in the STT3A gene, resulting in an arg329-to-cys (R329C) substitution. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing. The mutation is located around the STT3A catalytic site. A type 1 transferrin glycosylation profile was detected in the patients. S. cerevisiae cells transfected with the corresponding yeast Stt3 mutation (R328C) demonstrated protein (carboxypeptidase A) hypoglycosylation.
Dumax-Vorzet, A., Roboti, P., High, S. OST4 is a subunit of the mammalian oligosaccharyltransferase required for efficient N-glycosylation. J. Cell Sci. 126: 2595-2606, 2013. [PubMed: 23606741] [Full Text: https://doi.org/10.1242/jcs.115410]
Ghosh, A., Urquhart, J., Daly, S., Ferguson, A., Scotcher, D., Morris, A. A. M., Clayton-Smith, J. Phenotypic heterogeneity in a congenital disorder of glycosylation caused by mutations in STT3A. J. Child Neurol. 32: 560-575, 2017. [PubMed: 28424003] [Full Text: https://doi.org/10.1177/0883073817696816]
Hong, G., Deleersnijder, W., Kozak, C. A., Van Marck, E., Tylzanowski, P., Merregaert, J. Molecular cloning of a highly conserved mouse and human integral membrane protein (Itm1) and genetic mapping to mouse chromosome 9. Genomics 31: 295-300, 1996. [PubMed: 8838310] [Full Text: https://doi.org/10.1006/geno.1996.0051]
Knopf, J. D., Landscheidt, N., Pegg, C. L., Schulz, B. L., Kuhnle, N., Chao, C.-W., Huck, S., Lemberg, M. K. Intramembrane protease RHBDL4 cleaves oligosaccharyltransferase subunits to target them for ER-associated degradation. J. Cell Sci. 133: jcs243790, 2020. Note: Electronic Article. [PubMed: 32005703] [Full Text: https://doi.org/10.1242/jcs.243790]
Lissy, N. A., Bellacosa, A., Sonoda, G., Miller, P. D., Jhanwar, S. C., Testa, J. R. Isolation, characterization, and mapping to human chromosome 11q24-25 of a cDNA encoding a highly conserved putative transmembrane protein, TMC. Biochim. Biophys. Acta 1306: 137-141, 1996. [PubMed: 8634329] [Full Text: https://doi.org/10.1016/0167-4781(96)00025-5]
Shrimal, S., Ng, B. G., Losfeld, M.-E., Gilmore, R., Freeze, H. H. Mutations in STT3A and STT3B cause two congenital disorders of glycosylation. Hum. Molec. Genet. 22: 4638-4645, 2013. [PubMed: 23842455] [Full Text: https://doi.org/10.1093/hmg/ddt312]
Van Hul, W., Hong, G., Wauters, J., Van Hul, E., Nowak, N., Shows, T. B., Willems, P. J., Merregaert, J. Assignment of the human integral transmembrane protein 1 gene (ITM1) to human chromosome band 11q23.3 by in situ hybridization and YAC mapping. Cytogenet. Cell Genet. 74: 218-219, 1996. [PubMed: 8941377] [Full Text: https://doi.org/10.1159/000134417]
Wilson, M. P., Garanto, A., Pinto e Vairo, F., Ng, B. G., Ranatunga, W. K., Ventouratou, M., Baerenfaenger, M., Huijben, K., Thiel, C., Ashikov, A., Keldermans, L., Souche, E., and 23 others. Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings. Am. J. Hum. Genet. 108: 2130-2144, 2021. [PubMed: 34653363] [Full Text: https://doi.org/10.1016/j.ajhg.2021.09.012]