| *610308 | |||||||||||||||||||||
| UDP-GAL:BETA-GlcNAc BETA-1,3-GALACTOSYLTRANSFERASE-LIKE; B3GALTL | |||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||
| BETA-3-GLYCOSYLTRANSFERASE-LIKE; B3GTL BETA-1,3-GLUCOSYLTRANSFERASE; B3GLCT | |||||||||||||||||||||
| HGNC Approved Gene Symbol: B3GALTL | |||||||||||||||||||||
| Cytogenetic location: 13q12.3 Genomic coordinates (GRCh37): 13:31,774,111 - 31,906,412 (from NCBI) | |||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||
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| TEXT | |||||||||||||||||||||
| Description | |||||||||||||||||||||
| B3GALTL is a beta-1,3-glucosyltransferase involved in the synthesis of the unusual O-linked disaccharide glucosyl-beta-1,3-fucose-O- found on the thrombospondin (see THBS1; 188060) type-1 repeats (TSRs) of many biologically important proteins. Biosynthesis of glucosyl-beta-1,3-fucose-O- is initiated by protein O-fucosyltransferase-2 (POFUT2; 610249), which attaches the fucosyl residue to a serine or threonine within the TSR. B3GALTL subsequently transfers the glucose onto TSR-fucose (Hess et al., 2008). | |||||||||||||||||||||
| Cloning | |||||||||||||||||||||
| By EST database analysis and PCR of heart, brain, and kidney cDNA libraries, Heinonen et al. (2003) cloned B3GTL. The deduced 498-amino acid protein is a type II membrane protein with a 4-residue N-terminal cytoplasmic domain, a transmembrane domain, and a large C-terminal portion containing a stem region and a catalytic domain. The catalytic domains contains a triple-aspartate (DDD) motif at its core, a conserved pattern of cysteines, a C-terminal KDEL-like motif, and other residues and motifs conserved in beta-3-glycosyltransferases. Heinonen et al. (2003) identified B3GTL cDNAs with 3 types of 3-prime UTRs resulting from the use of different cleavage and polyadenylation sites. Northern blot analysis detected variable expression of 4.2- and 3.4-kb transcripts in all tissues examined. Sato et al. (2006) cloned human and mouse B3GLCT, and they also identified B3GLCT orthologs in fly and nematode databases. Like human B3GLCT, the 489-amino acid mouse protein has 3 B3GT domains and a C-terminal KDEL-like sequence (REEL). Quantitative real-time PCR of human tissues revealed ubiquitous B3GLCT expression, with highest levels in testis and uterus. Immunohistochemical and immunoprecipitation analysis of transfected COS-1 cells showed that human B3GLCT localized to the endoplasmic reticulum and was secreted into the culture medium. The C-terminal REEL sequence was required for retention in the ER. | |||||||||||||||||||||
| Gene Function | |||||||||||||||||||||
| Heinonen et al. (2003) found that human intestinal epithelial cells increased expression of B3GTL 3.1-fold following treatment with TGF-beta (TGFB1; 190180). Using a variety of radiolabeled uridine diphosphate (UDP) donors and monosaccharide acceptors, Sato et al. (2006) found that recombinant human B3GLCT exhibited glucosyltransferase activity only when UDP-glucose was used as the donor substrate and fucose-alpha-para-nitrophenyl was used as the acceptor substrate. B3GLCT showed glucosyltransferase activity toward H-antigen type 2 and Le(a), but not toward H-antigen type 1 and Le(x). It also showed glucosyltransferase activity toward a fucosylated TSR domain, but not a fucosylated EGF domain (see 131530). Mouse B3glct exhibited the same enzymatic activity as human B3GLCT. Kozma et al. (2006) showed that human B3GLCT transferred glucose to recombinant fucosylated TSR domain-4 (TSR4) amplified from rat F-spondin (SPON1; 604989). B3GLCT attached the glucose residue in a beta-1,3-linkage to the fucosyl residue of the fucosylated threonine in TSR4-fucose, and it strongly preferred UDP-glucose as the sugar donor. Mutation of the DDD motif within the putative catalytic domain of B3GLCT abolished its enzymatic activity. | |||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||
| Heinonen et al. (2003) determined that the B3GALTL gene contains 15 coding exons and spans about 132 kb. The sequence in the vicinity of a transcriptional initiator element contains no canonical TATA or CAAT boxes, but it is unusually GC rich and has several SP1 (189906)-binding sites. B3GALTL has multiple transcription start sites, and the proximal promoter has binding sites for several differentiation-specific factors that regulate expression in blood, cardiac, and epithelial cells. | |||||||||||||||||||||
| Mapping | |||||||||||||||||||||
| By genomic sequence analysis, Heinonen et al. (2003) mapped the B3GALTL gene to chromosome 13q12.3. | |||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||
| Peters-plus syndrome (261540) is an autosomal recessive disorder characterized by a variety of anterior eye-chamber defects, of which the Peters anomaly occurs most frequently. Other major symptoms are a disproportionate short stature, developmental delay, characteristic craniofacial features, and cleft lip and/or palate. To detect possible microrearrangements affecting the disease locus, Lesnik Oberstein et al. (2006) performed genomewide 1-Mb resolution array-based comparative genomic hybridization on genomic DNA of 2 brothers and 4 isolated patients who all carried the clinical diagnosis of Peters-plus syndrome. In both brothers, 2 adjacent BAC clones were found to be present in a single copy, representing an interstitial deletion of approximately 1.5 Mb on 13q12.3-q13.1. The B3GALTL gene, located in the region of deletion, was found to carry biallelic (homozygous or compound heterozygous) truncating mutations in all 20 tested patients, showing that Peters-plus syndrome is a monogenic, primarily single-mutation disorder. The 2 brothers carried on their nondeleted chromosome a point mutation (660+1G-A; 610308.0001) in the donor splice site of exon 8 of B3GALTL. The same mutation was present in single copy in the father, the deletion having been inherited from the mother. The homozygous 660+1G-A mutation was found in 16 of 18 patients studied. In 2 Dutch sibs, compound heterozygosity was found for the 660+1G-A mutation and a different mutation on the paternal allele in intron 5 of B3GALTL (347+5G-A; 610308.0002). SNP studies suggested that the mutation, observed not only in Dutch patients but also in Italian, Turkish, and English patients, represented a recurrent mutation, although some of the Dutch patients may have had a common ancestor. The mutation occurs at a site of a potentially methylated CpG dinucleotide, which could explain its recurrence. Reis et al. (2008) examined B3GALTL exons and flanking introns in 4 patients with typical Peters-plus syndrome and 4 patients with only some characteristic features of this syndrome. They identified mutations in the B3GALTL gene in all 4 patients with typical Peters-plus syndrome but in none of the 4 patients with some phenotypic overlap. The previously identified 660+1G-A mutation was identified in homozygous state in 2 of the 4 patients and in compound heterozygous state with novel mutations (459+1G-A, 610308.0003 and 230insT, 610308.0004) in the other 2. In 2 patients with Peters-plus syndrome, Dassie-Ajdid et al. (2009) identified homozygosity for the 459+1G-A mutation in one and compound heterozygosity for the recurrent 660+1G-A mutation and a missense mutation (610308.0005) in the other. Screening of the B3GALTL gene in 2 additional patients who had Peters anomaly (604229) and psychomotor delay but who did not meet other Peters-plus syndrome criteria did not reveal any mutations. | |||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||
| Table View | |||||||||||||||||||||
| .0001 PETERS-PLUS SYNDROME | |||||||||||||||||||||
| B3GALTL, IVS8, G-A, +1 [dbSNP:rs80338851] | |||||||||||||||||||||
| In 2 sibs with Peters-plus syndrome (261540) who had a microdeletion encompassing the B3GALTL gene on their maternal allele, Lesnik Oberstein et al. (2006) identified a 660+1G-A transition in the donor splice site of exon 8 of the B3GALTL gene on the paternal allele. Targeted sequencing analysis in an additional 18 Peters-plus patients from 15 families revealed homozygosity for the splice site mutation in 16 patients; in the remaining 2 patients (Dutch sibs), the mutation was found in compound heterozygosity with another splice site mutation (610308.0002). Fourteen patients were Dutch whites, and the other patients were Turkish, British, Arab, or Indian. Using an immunopurification-mass spectroscopy method, Hess et al. (2008) found that Peters-plus patients carrying the 660+1G-A mutation in B3GALTL showed only the fucosyl-O- modification in all 4 O-fucosylation sites of the reporter protein properdin (PFC; 300383). In contrast, properdin from heterozygous relatives and a healthy volunteer showed the glucosyl-beta-1,3-fucose-O- modification. Reis et al. (2008) identified homozygosity for the common 660+1G-A mutation in the B3GALTL gene in 2 patients, 1 Caucasian and 1 Hispanic, with Peter-plus syndrome. In 2 other Caucasian patients with this disorder, they identified compound heterozygosity for this mutation and either IVS6+1G-A (610308.0003) or 230insT (610308.0004). In a Sri Lankan patient with Peters-plus syndrome, Dassie-Ajdid et al. (2009) identified compound heterozygosity for the recurrent 660+1G-A mutation and a missense mutation (610308.0005) in the B3GALTL gene. | |||||||||||||||||||||
| .0002 PETERS-PLUS SYNDROME | |||||||||||||||||||||
| B3GALTL, IVS5, G-A, +5 [dbSNP:rs80338850] | |||||||||||||||||||||
| In 2 Dutch sibs with Peters-plus syndrome (261540), Lesnik Oberstein et al. (2006) found compound heterozygosity for the 660+1G-A mutation (610308.0001) and for another donor splice site mutation, 347+5G-A, in the B3GALTL gene. | |||||||||||||||||||||
| .0003 PETERS-PLUS SYNDROME | |||||||||||||||||||||
| B3GALTL, IVS6, G-A, +1 | |||||||||||||||||||||
| In a Caucasian patient with Peters-plus syndrome (261540), Reis et al. (2008) identified compound heterozygosity for 2 mutations in the B3GALTL gene: the common 660+1G-A mutation (610308.0001) and a 459+1G-A mutation in exon 6. The mutation is predicted to alter splicing, leading to a truncated protein product or nonsense-mediated decay. The mutation was not found in 180 control samples from unaffected individuals. In an infant with Peters-plus syndrome, Dassie-Ajdid et al. (2009) identified homozygosity for the 459+1G-A mutation in the B3GALTL gene. The parents were each heterozygous for the mutation. | |||||||||||||||||||||
| .0004 PETERS-PLUS SYNDROME | |||||||||||||||||||||
| B3GALTL, 1-BP INS, 230T | |||||||||||||||||||||
| In a Caucasian patient with Peters-plus syndrome (261540), Reis et al. (2008) identified compound heterozygosity for 2 mutations in the B3GALTL gene: the common 660+1G-A mutation (610308.0001) and a 1-bp insertion (230insT) in exon 4. The mutation is predicted to alter splicing, leading to a truncated protein product or nonsense-mediated decay. The mutation was not found in 180 control samples from unaffected individuals. | |||||||||||||||||||||
| .0005 PETERS-PLUS SYNDROME | |||||||||||||||||||||
| B3GALTL, GLY393GLU | |||||||||||||||||||||
| In a Sri Lankan patient with Peters-plus syndrome (261540), Dassie-Ajdid et al. (2009) identified compound heterozygosity for the recurrent 660+1G-A mutation (610308.0001) and a 1178G-A transition in exon 13 of the B3GALTL gene, resulting in a gly393-to-glu (G393E) substitution at a conserved residue. The parents were each heterozygous for 1 of the mutations. | |||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||
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