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Other entities represented in this entry:
HGNC Approved Gene Symbol: SLC35A2
SNOMEDCT: 771516000;
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:48,903,183-48,911,958 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Congenital disorder of glycosylation, type IIm | 300896 | Somatic mosaicism; X-linked dominant | 3 |
For glycosylation reactions to proceed in vivo, nucleotide sugars must be transported via a translocation mechanism from cytosol or nucleus into Golgi vesicles where glycosyltransferases function in an orderly fashion. Defects in glycosylation have been identified in Chinese hamster cells and mouse cells. The mutation in mouse cells was found to be complemented by the human X chromosome. Hara et al. (1993) cloned a segment of the human gene encoding UDP-galactose translocator by genetic complementation of the defective Had-1 mutant of mouse FM3A cells.
Ishida et al. (1996) identified an SLC35A2 splice variant, which they termed UGT2, that encodes a protein 3 amino acids longer than the 393-amino acid variant (UGT1) identified by Miura et al. (1996); the 2 proteins differ only over the last 8 residues. The UGT2 variant was able to complement the galactose transporter deficiency of the mouse Had-1 cell line.
Carette et al. (2009) used insertional mutagenesis to develop a screening method to generate null alleles in a human cell line haploid for all chromosomes except chromosome 8. Using this approach, Carette et al. (2009) identified host factors essential for infection with influenza, including SLC35A2. The SLC35A2 gene product transports uridine 5-prime-diphosphate-galactose from the cytoplasm to the Golgi, where it serves as a glycosyl donor important for the generation of glycans to be modified with sialic acids.
Using fluorescence in situ hybridization, Hara et al. (1993) mapped the SLC35A2 gene to chromosome Xp11.23-p11.22. Since the Wiskott-Aldrich syndrome (301000) maps to the same region and since CD43, a cell-surface sialoglycoprotein, is defective in this disorder, implication of the UGTL gene in that disorder was suggested.
In 3 unrelated patients with congenital disorder of glycosylation type II (CDG2M; 300896), Ng et al. (2013) identified 3 different de novo mutations in the SLC35A2 gene. Two boys carried a hemizygous mutation in the somatic mosaic state (314375.0001, 314375.0002), whereas the girl carried a heterozygous mutation (314375.0003). Ng et al. (2013) hypothesized that retention of a functional SLC35A2 allele may be required for survival. Laboratory studies of the patients showed an abnormal serum transferrin pattern with loss of galactose and sialic acid from multiple branches of complex type N-glycans. Patient cells also showed reduced Golgi transport of UDP-galactose compared to controls. However, the presence of partially galactosylated glycans on serum glycoproteins suggested the possible existence of a previously unrecognized UDP-gal transporter. All patients showed normalization of the abnormal transferrin pattern with age without clinical improvement, suggesting that the mutant alleles are selected against during infancy and that there is a limited diagnostic window for the relevant test.
In 3 unrelated Japanese girls with developmental and epileptic encephalopathy-22 (DEE22; 300896) clinically diagnosed as West syndrome, Kodera et al. (2013) identified 3 different de novo heterozygous mutations in the SLC35A2 gene (314375.0004-314375.0006). The first 2 mutations were found by whole-exome sequencing; the third patient was 1 of a cohort of 328 patients with a similar disorder who underwent targeted SLC35A2 sequencing. Two of the mutations resulted in truncated proteins, suggesting a loss of function, and 1 was a missense mutation with no functional studies. Although none of the patients had evidence of abnormal glycosylation of serum proteins, and 2 had favorably skewed X-inactivation, Kodera et al. (2013) hypothesized that neurons may express the mutant allele and thus have defective galactosylation.
By whole-exome sequencing in 2 patients with CDG2M, Kasapkara et al. (2021) identified de novo mutations in the SLC35A2 gene (I181V, 314375.0007; S308F, 314375.0008). Transferrin isoelectric focusing was normal in both patients.
Ng et al. (2019) identified 30 heterozygous mutations in the SLC35A2 gene, 36 of which were novel, in 30 unrelated patients with CDG2M. The mutations were identified by next-generation sequencing in 29 patients and by Sanger sequencing of the SLC35A2 gene following an abnormal carbohydrate-deficient transferrin test in 1 patient. The mutations included 15 missense mutations, 7 out-of-frame insertion/deletions, 4 nonsense mutations, 2 in-frame deletions, 1 splice site mutation, and 1 start codon loss. Only 1 patient was male (CDG-0460), and he had an L315P mutation that did not appear to be mosaic.
In a 3-year-old boy (CDG-341) with congenital disorder of glycosylation type II (CDG2M; 300896), Ng et al. (2013) identified a de novo hemizygous c.15_91+48delinsA mutation (c.15_91+48delinsA, NM_001042498.2) in the SLC35A2 gene, resulting in a frameshift and premature termination (Gly8SerfsTer9). The mutation was present in the somatic mosaic state. The mutation was identified by Sanger sequencing of candidate genes encoding proteins in the glycosylation pathway and was not found in several large control databases.
In a 6-year-old boy (CDG-352) with congenital disorder of glycosylation type IIm (CDG2M; 300896), Ng et al. (2013) identified a de novo hemizygous c.991G-A transition (c.991G-A, NM_001042493.2) in the SLC35A2 gene, resulting in a val331-to-ile (V331I) substitution and predicted to cause improper positioning in the membrane. The mutation was present in the somatic mosaic state in the patient and was not found in several large control databases.
In a 3-year-old girl (CDG-348) with congenital disorder of glycosylation type IIm (CDG2M; 300896), Ng et al. (2013) identified a de novo heterozygous c.3G-A transition (c.3G-A, NM_001042498.2) in the SLC35A2 gene, predicted to eliminate the normal translational start site. The mutation was not found in several large control databases. The parents of the girl had had 2 previous spontaneous abortions.
In an 8-year-old Japanese girl (patient 1) with developmental and epileptic encephalopathy-22 (DEE22; 300896) diagnosed clinically as West syndrome, Kodera et al. (2013) identified a de novo heterozygous 2-bp deletion (c.433delTA, NM_005660.1) in the SLC35A2 gene, resulting in a frameshift and premature termination (Tyr145ProfsTer76) within the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 408 in-house control exomes. X-chromosome inactivation studies showed a markedly skewed pattern, with expression only of the wildtype allele. Expression of the mutation in mouse neuronal cells showed very low levels of protein expression compared to wildtype, suggesting a loss of function. The patient had onset of tonic seizures at 6 days of age, followed by seizures associated with hypsarrhythmia at 2 months.
In a 12-year-old Japanese girl (patient 2) with developmental and epileptic encephalopathy-22 (DEE22; 300896) clinically diagnosed as West syndrome, Kodera et al. (2013) identified a de novo heterozygous 1-bp deletion (c.972delT, NM_005660.1) in the SLC35A2 gene, resulting in a frameshift and premature termination (Phe324LeufsTer25) within the transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 408 in-house control exomes. X-chromosome inactivation studies showed a markedly skewed pattern, with expression only of the wildtype allele. Expression of the mutation in mouse neuronal cells showed that the mutant protein was expressed abnormally in the cytosol and did not localize properly to the Golgi apparatus, suggesting a loss of function. The patient had onset of infantile spasms at age 1 month.
In a 10-year-old Japanese girl (patient 3) with developmental and epileptic encephalopathy-22 (DEE22; 300896) and clinically diagnosed as West syndrome, Kodera et al. (2013) identified a de novo heterozygous c.638C-T transition (c.638C-T, NM_005660.1) in the SLC35A2 gene, resulting in a ser213-to-phe (S213F) substitution at a highly conserved residue in the transmembrane domain. The mutation was not found in the Exome Variant Server database or in 408 in-house control exomes. The patient was 1 of a cohort of 328 patients with a similar disorder who underwent targeted SLC35A2 sequencing. The S213F mutant protein showed normal cellular localization, but other functional studies were not performed. The patient had onset of infantile spasms at 3 months of age.
In a 4-year-old boy with congenital disorder of glycosylation type IIm (CDG2M; 300896), Kasapkara et al. (2021) identified a de novo hemizygous c.541A-G transition (c.541A-G, NM_001042498.3) in the SLC35A2 gene, resulting in an ile181-to-val (I181V) substitution. The mutation was identified by whole-exome sequencing. Functional studies were not performed.
In a 5-year-old girl with congenital disorder of glycosylation type IIm (CDG2M; 300896), Kasapkara et al. (2021) identified a de novo heterozygous c.923C-T transition (c.923C-T, NM_001042498.3) in the SLC35A2 gene, resulting in a ser308-to-phe (S308F) substitution. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing.
Carette, J. E., Guimaraes, C. P., Varadarajan, M., Park, A. S., Wuethrich, I., Godarova, A., Kotecki, M., Cochran, B. H., Spooner, E., Ploegh, H. L., Brummelkamp, T. R. Haploid genetic screens in human cells identify host factors used by pathogens. Science 326: 1231-1235, 2009. [PubMed: 19965467] [Full Text: https://doi.org/10.1126/science.1178955]
Hara, T., Yamauchi, M., Takahashi, E., Hoshino, M., Aoki, K., Ayusawa, D., Kawakita, M. The UDP-galactose translocator gene is mapped to band Xp11.23-p11.22 containing the Wiskott-Aldrich syndrome locus. Somat. Cell Molec. Genet. 19: 571-575, 1993. [PubMed: 8128316] [Full Text: https://doi.org/10.1007/BF01233383]
Ishida, N., Miura, N., Yoshioka, S., Kawakita, M. Molecular cloning and characterization of a novel isoform of the human UDP-galactose transporter, and of related complementary DNAs belonging to the nucleotide-sugar transporter gene family. J. Biochem. 120: 1074-1078, 1996. [PubMed: 9010752] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a021523]
Kasapkara, C. S., Ceylan, A. C., Ozyurek, H., Karakaya Molla, G. K., Civelek Urey, B., Kireker Koylu, O., Kucukcongar Yavas, A., Sonmez, F. M. SLC35A2-CDG: novel variants with two ends of the spectrum. J. Pediat. Endocr. Metab. 34: 1185-1189, 2021. [PubMed: 34161696] [Full Text: https://doi.org/10.1515/jpem-2021-0292]
Kodera, H., Nakamura, K., Osaka, H., Maegaki, Y., Haginoya, K., Mizumoto, S., Kato, M., Okamoto, N., Iai, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Nakashima, M., Miyake, N., Hayasaka, K., Sugahara, K., Yuasa, I., Wada, Y., Matsumoto, N., Saitsu, H. De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy. Hum. Mutat. 34: 1708-1714, 2013. [PubMed: 24115232] [Full Text: https://doi.org/10.1002/humu.22446]
Miura, N., Ishida, N., Hoshino, M., Yamauchi, M., Hara, T., Ayusawa, D., Kawakita, M. Human UDP-galactose translocator: molecular cloning of a complementary DNA that complements the genetic defect of a mutant cell line deficient in UDP-galactose translocator. J. Biochem. 120: 236-241, 1996. [PubMed: 8889805] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a021404]
Ng, B. G., Buckingham, K. J., Raymond, K., Kircher, M., Turner, E. H., He, M., Smith, J. D., Eroshkin, A., Szybowska, M., Losfeld, M. E., Chong, J. X., Kozenko, M., Li, C., Patterson, M. C., Gilbert, R. D., Nickerson, D. A., Shendure, J., Bamshad, M. J., University of Washington Center for Mendelian Genomics, Freeze, H. H. Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am. J. Hum. Genet. 92: 632-636, 2013. [PubMed: 23561849] [Full Text: https://doi.org/10.1016/j.ajhg.2013.03.012]
Ng, B. G., Sosicka, P., Agadi, S., Almannai, M., Bacino, C. A., Barone, R., Botto, L. D., Burton, J. E., Carlston, C., Chung, B. H.-Y., Cohen, J. S., Coman, D., and 57 others. SLC35A2-CDG: functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported individuals. Hum. Mutat. 40: 908-925, 2019. [PubMed: 30817854] [Full Text: https://doi.org/10.1002/humu.23731]