* 608605

OLIGOSACCHARYLTRANSFERASE COMPLEX, CATALYTIC SUBUNIT STT3B; STT3B


Alternative titles; symbols

STT3, S. CEREVISIAE, HOMOLOG OF, B
SOURCE OF IMMUNODOMINANT MAJOR HISTOCOMPATIBILITY COMPLEX-ASSOCIATED PEPTIDES
SOURCE OF IMMUNODOMINANT MHC-ASSOCIATED PEPTIDES; SIMP


HGNC Approved Gene Symbol: STT3B

Cytogenetic location: 3p23     Genomic coordinates (GRCh38): 3:31,532,925-31,637,616 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
3p23 Congenital disorder of glycosylation, type Ix 615597 AR 3

TEXT

Description

The STT3B 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 STT3A; 601134) 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).


Cloning and Expression

B6(dom1) is a highly immunogenic minor histocompatibility antigen in mice. Using the sequence of B6(dom1) suggested by Edman degradation analysis to search protein and cDNA databases, McBride et al. (2002) identified a candidate polymorphic mouse gene, which they termed Simp. The B6(dom1) antigen corresponds to amino acids 770 to 778 of the 823-amino acid Simp protein, and analysis of cytotoxic T-lymphocyte activity in different mouse strains confirmed the presence of a polymorphism at amino acid 776. By searching a genomic database and degenerate PCR analysis, McBride et al. (2002) obtained a human cDNA encoding SIMP. The 826-amino acid human protein shares 97% identity with the mouse protein. Sequence analysis of SIMP cDNA from 14 individuals failed to reveal polymorphism of human SIMP.


Mapping

By genomic sequence analysis, McBride et al. (2002) mapped the SIMP gene to chromosome 3p22.3, a region that shows homology of synteny to the telomeric end of mouse chromosome 9, where the mouse Simp gene is localized.


Gene Function

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.


Molecular Genetics

In a boy, born of consanguineous Iraqi parents, with congenital disorder of glycosylation type Ix (CDG1X; 615597), Shrimal et al. (2013) identified a homozygous mutation in the STT3B gene (608605.0001). The mutation was found by homozygosity mapping and candidate gene sequencing. The patient had severely delayed psychomotor development with microcephaly, hypotonia, seizures, and optic atrophy, and died at age 4 years. Serum transferrin showed only a mildly abnormal type I pattern of glycosylation. Patient cells showed no STT3B mRNA and severely reduced protein expression. Patient cells also showed incomplete N-glycosylation of a GFP biomarker that was complemented by wildtype STT3B, as well as lower glycosylation of the STT3B substrates SHBG (182205) and beta-glucuronidase (GUSB; 611499) compared to control cells.

In a Turkish boy, born of consanguineous parents, with CDG1X, Kilic and Akkus (2020) identified a homozygous missense mutation in the STT3B gene (S13W; 608605.0002). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Functional studies were not performed.


ALLELIC VARIANTS ( 2 Selected Examples):

.0001 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ix

STT3B, c.1539+20G-T
  
RCV000088685

In a boy, born of consanguineous Iraqi parents, with congenital disorder of glycosylation type Ix (CDG1X; 615597), Shrimal et al. (2013) identified a homozygous G-to-T transversion in an intron of the STT3B gene (c.1539+20G-T). 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. Patient cells showed no STT3B mRNA and severely reduced protein expression. The patient had severe developmental and congenital anomalies, including microcephaly, failure to thrive, lack of visual tracking and optic nerve hypoplasia, cerebellar atrophy, seizures, hypotonia, liver involvement, thrombocytopenia, micropenis, hypoplastic scrotum, and undescended testes. He died at age 4 years. Serum transferrin showed an only slightly abnormal glycosylation pattern. Patient cells showed incomplete N-glycosylation of a GFP biomarker complemented by wildtype STT3B as well as lower glycosylation of the STT3B substrates SHBG (182205) and beta-glucuronidase (GUSB; 611499) compared to control cells.


.0002 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ix

STT3B, SER13TRP
  
RCV002248435

In a boy, born of consanguineous Turkish parents, with congenital disorder of glycosylation type Ix (CDG1X; 615597), Kilic and Akkus (2020) identified a homozygous c.38C-G transversion in the STT3B gene, resulting in a ser13-to-trp (S13W) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Functional studies were not performed.


REFERENCES

  1. 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, images, related citations] [Full Text]

  2. Kilic, B., Akkus, N. Novel mutation and severe respiratory failure in congenital disorders of glycosylation type Ix. Turk. J. Pediat. 62: 114-118, 2020. [PubMed: 32253875, related citations] [Full Text]

  3. McBride, K., Baron, C., Picard, S., Martin, S., Boismenu, D., Bell, A., Bergeron, J., Perreault, C. The model B6(dom1) minor histocompatibility antigen is encoded by a mouse homolog of the yeast STT3 gene. Immunogenetics 54: 562-569, 2002. [PubMed: 12439619, related citations] [Full Text]

  4. 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, images, related citations] [Full Text]


Hilary J. Vernon - updated : 05/19/2022
Bao Lige - updated : 06/29/2020
Cassandra L. Kniffin - updated : 1/9/2014
Creation Date:
Paul J. Converse : 4/23/2004
carol : 05/19/2022
mgross : 09/17/2020
mgross : 06/29/2020
carol : 06/15/2014
carol : 1/13/2014
mgross : 1/10/2014
mcolton : 1/10/2014
ckniffin : 1/9/2014
mgross : 4/23/2004

* 608605

OLIGOSACCHARYLTRANSFERASE COMPLEX, CATALYTIC SUBUNIT STT3B; STT3B


Alternative titles; symbols

STT3, S. CEREVISIAE, HOMOLOG OF, B
SOURCE OF IMMUNODOMINANT MAJOR HISTOCOMPATIBILITY COMPLEX-ASSOCIATED PEPTIDES
SOURCE OF IMMUNODOMINANT MHC-ASSOCIATED PEPTIDES; SIMP


HGNC Approved Gene Symbol: STT3B

SNOMEDCT: 733112007;  


Cytogenetic location: 3p23     Genomic coordinates (GRCh38): 3:31,532,925-31,637,616 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
3p23 Congenital disorder of glycosylation, type Ix 615597 Autosomal recessive 3

TEXT

Description

The STT3B 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 STT3A; 601134) 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).


Cloning and Expression

B6(dom1) is a highly immunogenic minor histocompatibility antigen in mice. Using the sequence of B6(dom1) suggested by Edman degradation analysis to search protein and cDNA databases, McBride et al. (2002) identified a candidate polymorphic mouse gene, which they termed Simp. The B6(dom1) antigen corresponds to amino acids 770 to 778 of the 823-amino acid Simp protein, and analysis of cytotoxic T-lymphocyte activity in different mouse strains confirmed the presence of a polymorphism at amino acid 776. By searching a genomic database and degenerate PCR analysis, McBride et al. (2002) obtained a human cDNA encoding SIMP. The 826-amino acid human protein shares 97% identity with the mouse protein. Sequence analysis of SIMP cDNA from 14 individuals failed to reveal polymorphism of human SIMP.


Mapping

By genomic sequence analysis, McBride et al. (2002) mapped the SIMP gene to chromosome 3p22.3, a region that shows homology of synteny to the telomeric end of mouse chromosome 9, where the mouse Simp gene is localized.


Gene Function

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.


Molecular Genetics

In a boy, born of consanguineous Iraqi parents, with congenital disorder of glycosylation type Ix (CDG1X; 615597), Shrimal et al. (2013) identified a homozygous mutation in the STT3B gene (608605.0001). The mutation was found by homozygosity mapping and candidate gene sequencing. The patient had severely delayed psychomotor development with microcephaly, hypotonia, seizures, and optic atrophy, and died at age 4 years. Serum transferrin showed only a mildly abnormal type I pattern of glycosylation. Patient cells showed no STT3B mRNA and severely reduced protein expression. Patient cells also showed incomplete N-glycosylation of a GFP biomarker that was complemented by wildtype STT3B, as well as lower glycosylation of the STT3B substrates SHBG (182205) and beta-glucuronidase (GUSB; 611499) compared to control cells.

In a Turkish boy, born of consanguineous parents, with CDG1X, Kilic and Akkus (2020) identified a homozygous missense mutation in the STT3B gene (S13W; 608605.0002). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Functional studies were not performed.


ALLELIC VARIANTS 2 Selected Examples):

.0001   CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ix

STT3B, c.1539+20G-T
SNP: rs587777217, ClinVar: RCV000088685

In a boy, born of consanguineous Iraqi parents, with congenital disorder of glycosylation type Ix (CDG1X; 615597), Shrimal et al. (2013) identified a homozygous G-to-T transversion in an intron of the STT3B gene (c.1539+20G-T). 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. Patient cells showed no STT3B mRNA and severely reduced protein expression. The patient had severe developmental and congenital anomalies, including microcephaly, failure to thrive, lack of visual tracking and optic nerve hypoplasia, cerebellar atrophy, seizures, hypotonia, liver involvement, thrombocytopenia, micropenis, hypoplastic scrotum, and undescended testes. He died at age 4 years. Serum transferrin showed an only slightly abnormal glycosylation pattern. Patient cells showed incomplete N-glycosylation of a GFP biomarker complemented by wildtype STT3B as well as lower glycosylation of the STT3B substrates SHBG (182205) and beta-glucuronidase (GUSB; 611499) compared to control cells.


.0002   CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ix

STT3B, SER13TRP
SNP: rs1696976315, ClinVar: RCV002248435

In a boy, born of consanguineous Turkish parents, with congenital disorder of glycosylation type Ix (CDG1X; 615597), Kilic and Akkus (2020) identified a homozygous c.38C-G transversion in the STT3B gene, resulting in a ser13-to-trp (S13W) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Functional studies were not performed.


REFERENCES

  1. 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]

  2. Kilic, B., Akkus, N. Novel mutation and severe respiratory failure in congenital disorders of glycosylation type Ix. Turk. J. Pediat. 62: 114-118, 2020. [PubMed: 32253875] [Full Text: https://doi.org/10.24953/turkjped.2020.01.016]

  3. McBride, K., Baron, C., Picard, S., Martin, S., Boismenu, D., Bell, A., Bergeron, J., Perreault, C. The model B6(dom1) minor histocompatibility antigen is encoded by a mouse homolog of the yeast STT3 gene. Immunogenetics 54: 562-569, 2002. [PubMed: 12439619] [Full Text: https://doi.org/10.1007/s00251-002-0502-4]

  4. 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]


Contributors:
Hilary J. Vernon - updated : 05/19/2022
Bao Lige - updated : 06/29/2020
Cassandra L. Kniffin - updated : 1/9/2014

Creation Date:
Paul J. Converse : 4/23/2004

Edit History:
carol : 05/19/2022
mgross : 09/17/2020
mgross : 06/29/2020
carol : 06/15/2014
carol : 1/13/2014
mgross : 1/10/2014
mcolton : 1/10/2014
ckniffin : 1/9/2014
mgross : 4/23/2004