Alternative titles; symbols
HGNC Approved Gene Symbol: B3GALT6
SNOMEDCT: 1208342001, 1251499005, 1286833006;
Cytogenetic location: 1p36.33 Genomic coordinates (GRCh38) : 1:1,232,237-1,235,041 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.33 | Al-Gazali syndrome | 609465 | Autosomal recessive | 3 |
| Ehlers-Danlos syndrome, spondylodysplastic type, 2 | 615349 | Autosomal recessive | 3 | |
| Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures | 271640 | Autosomal recessive | 3 |
Glycosaminoglycan biosynthesis initiates with the formation of a linkage tetrasaccharide that serves as a primer, followed by sequential transfer of monosaccharide residues from the corresponding nucleotide sugars starting at the reducing end. B3GALNT6 (EC 2.4.1.134) forms a galactose (Gal)-beta-1,3-Gal linkage via the transfer of Gal from UDP-Gal to a terminal beta-linked Gal residue and functions in the synthesis of heparan sulfate and chondroitin sulfate (Bai et al., 2001).
By searching an EST database for sequences similar to mouse beta-1,3-galactosyltransferases (see B3GALT1, 603093), followed by screening a human fetal brain cDNA library and a newborn mouse brain cDNA library, Bai et al. (2001) cloned human and mouse B3GALT6, which they designated GALTII. The deduced human and mouse proteins contain 329 and 325 amino acids, respectively. GALTII is a typical type II transmembrane protein, with a transmembrane domain near the N terminus and a C-terminal galactosyltransferase domain containing a conserved cysteine residue. Northern blot analysis detected variable expression of transcripts of about 1.6, 2.4, and 3.3 kb in all 16 human tissues examined. Fluorescence-tagged GALTII colocalized with alpha-mannosidase II (MAN2A1; 154582), a marker of the medial Golgi. Bai et al. (2001) noted that the sequence and expression pattern of B3GALT6 had erroneously been reported as that of B3GNT2 (605581) in a previous publication (Zhou et al., 1999) due to a clerical error. The correct B3GNT2 sequence and expression pattern were provided in an erratum.
Bai et al. (2001) found that human GALTII expressed in insect cells showed strict requirement for UDP-Gal as a Gal donor. For a substrate, it reacted strongly with Gal-beta-1,4-xylosyl-beta-O-benzyl, which is found in the linkage region of glycosaminoglycans. It also used simple beta-galactosides and other glycans with terminal beta-linked Gal residues. Knockdown of GALTII in HeLa cells inhibited synthesis of both heparan sulfate and chondroitin sulfate.
Bai et al. (2001) determined that B3GALT6 is a single-exon gene.
By genomic sequence analysis, Bai et al. (2001) mapped the B3GALT6 gene to chromosome 1p36.3. They mapped the mouse B3galt6 gene to a region of chromosome 4E2 that shares homology of synteny with human chromosome 1p36.3.
Spondyloepimetaphyseal Dysplasia with Joint Laxity, Type 1, with or without Fractures
By next-generation sequencing in 7 individuals, including 2 sibs, with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640) from 5 unrelated Japanese families and a Singapore/Japanese family, Nakajima et al. (2013) identified possible mutations in the B3GALT6 gene. By direct sequencing of this gene in these 7 patients and an additional patient with JEMDJL1 from a Vietnamese family, they identified compound heterozygous missense mutations in all but 1 in whom a second mutation was not found (615291.0001-615291.0006). One of the mutations (M1?; 615291.0001) was found in 5 of the 7 families. None of the mutations were found in 200 ethnically matched controls or in public databases, including the 1000 Genomes Project database. Immunocytochemical studies of mutant proteins showed subcellular mislocalization of all but 2 (D156N, 615291.0003 and C300S, 615291.0004). Galt-II activities of all mutant proteins were significantly decreased compared to wildtype, indicating loss of function. There were no significant differences in GALT-II activities between wildtype and a common B3GALT6 polymorphism (rs12085009). Biochemical studies using patient lymphoblastoid cells showed a decrease of heparan sulfate and a paradoxical increase of chondroitin sulfate and dermatan sulfate on the cell surface.
By homozygosity mapping and candidate gene sequence analysis in 3 unrelated Iranian families segregating SEMDJL1 with fractures, Malfait et al. (2013) identified homozygous or compound heterozygous mutations in the B3GALT6 gene (615291.0012-615291.0014), which segregated with the disorder in each family. Patient fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming B3GALT6 loss of function. Dermal electron microscopy showed abnormalities in collagen fibril organization. A strong reduction in heparan sulfate level was also observed, indicating that B3GALT6 deficiency alters synthesis of both main types of glycosaminoglycans. An in vitro wound healing assay revealed a significant delay in fibroblasts from 2 index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo.
Ehlers-Danlos Syndrome, Spondylodysplastic Type, 2
Because some of the patients with SEMDJL1 in whom they had identified mutations in the B3GALT6 gene had some overlapping features with a progeroid form of Ehlers-Danlos syndrome (EDSSPD2; 615349), Nakajima et al. (2013) performed Sanger sequencing of the B3GALT6 gene in 4 patients from 3 families who did not have a mutation in the B4GALT7 gene (604327). All 4 patients were found to be compound heterozygous for a frameshift and a missense mutation in the B3GALT6 gene (615291.0007-615291.0011). A missense mutation that was common in 2 EDSSPD2 families (S309T; 615291.0008) was found to have significantly decreased GalT-II activities compared to wildtype, indicating loss of function. None of the mutations were found in 200 ethnically matched controls or in public databases, including the 1000 Genomes Project database.
Using whole-exome, panel, and direct gene sequencing of 12 patients from 9 families with EDSSPD2, Van Damme et al. (2018) identified 8 compound heterozygous mutations and 1 homozygous (615291.0015) mutation in the B3GALT6 gene, including 11 missense variants, 2 frameshift variants, a deletion of 19 amino acids, and a start codon alteration. Most mutations were located in the luminal domain. In families in which parental DNA was available, mutations segregated as expected. Studies in fibroblasts showed that these mutations reduced the amount and activity of B3GALT6, which in turn reduced glycosaminoglycan synthesis and produced ultrastructural abnormalities in collagen fibril organization.
Al-Gazali Syndrome
In an infant with Al-Gazali syndrome (ALGAZ; 609465), Sellars et al. (2014) identified compound heterozygous missense mutations in the B3GALT6 gene (S159Y, 615291.0016; E265D, 615291.0017). The mutations, which were found by exome sequencing, segregated with the disorder in the family.
In 1 of the Palestinian infants with Al-Gazali syndrome reported by al-Gazali et al. (1999), Ben-Mahmoud et al. (2018) identified homozygosity for a missense mutation in the B3GALT6 gene (C206W; 615291.0018). The parents were heterozygous for the mutation.
In 5 affected individuals from 4 families with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640), Nakajima et al. (2013) identified compound heterozygosity for 2 mutations in the B3GALT6 gene: a c.1A-G transition resulting in a met1? substitution and another missense mutation. Four of the families were Japanese and 1 was Singapore/Japanese. In another affected Japanese patient, the mutation was found in heterozygous state. The Met1? mutation resulted in a mutant B3GALT6 protein with a molecular weight approximately 4 kD lower than the wildtype protein, suggesting that translation initiation at the second ATG of the coding sequence, at position c.124, would become the initiation codon, probably resulting in an N-terminal deletion of 41 amino acids (Met1_Ala41del), in the same open reading frame that contains the transmembrane domain. Immunofluorescence studies showed that the mutant protein mislocalized to the nucleus and cytoplasm, indicating that the protein was functionally null. The mutation was not detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
In affected individuals from 3 Japanese families and 1 Vietnamese family with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640), Nakajima et al. (2013) identified compound heterozygosity for 2 missense mutations in the B3GALT6 gene, one of which was a c.694C-T transition resulting in an arg232-to-cys (R232C) substitution. The mutation was not detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
In a Japanese patient with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640), Nakajima et al. (2013) identified compound heterozygosity for 2 missense mutations in the B3GALT6 gene: a c.466G-A transition resulting in an asp156-to-asn (D156N) substitution, and a Met1? substitution (615291.0001). Neither mutation was detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
In a Japanese patient with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640), Nakajima et al. (2013) identified compound heterozygosity for 2 mutations in the B3GALT6 gene: a c.899G-C transversion resulting in a cys300-to-ser (C300S) substitution, and an R232C substitution (615291.0002). Neither mutation was detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
In a patient with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640) from a Singapore/Japanese family, Nakajima et al. (2013) identified compound heterozygosity for 2 mutations in the B3GALT6 gene: a c.193A-G transition resulting in a ser65-to-gly (S65G) substitution, and a met1? substitution (615291.0001). Neither mutation was detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
In a Vietnamese patient with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640), Nakajima et al. (2013) identified compound heterozygosity for 2 mutations in the B3GALT6 gene: a c.200C-T transition resulting in a pro67-to-leu substitution, and an R232C substitution (615291.0002). Neither mutation was detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
In an Italian patient with spondylodysplastic Ehlers-Danlos syndrome-2 (EDSSPD2; 615349), Nakajima et al. (2013) identified compound heterozygosity for 2 mutations in the B3GALT6 gene: a 1-bp deletion (c.353delA) resulting in a frameshift (Asp118AlafsTer160), and a ser309-to-thr (S309T; 615291.0008) substitution. Neither mutation was detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
In 2 affected members of an Italian/Canadian family with spondylodysplastic Ehlers-Danlos syndrome-2 (EDSSPD2; 615349), Nakajima et al. (2013) identified compound heterozygosity for 2 mutations in the B3GALT6 gene: a 925T-A transversion resulting in a ser309-to-thr (S309T) substitution, and a 1-bp deletion (c.588delG; 615291.0009) resulting in a frameshift (Arg197AlafsTer81). Neither mutation was detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
Nakajima et al. (2013) also detected this mutation in compound heterozygosity with a c.353delA mutation (615291.0007) in an Italian patient with EDSSPD2.
For discussion of the 1-bp deletion in the B3GALT6 gene (c.588delG) that was found in compound heterozygous state in patients with spondylodysplastic Ehlers-Danlos syndrome-2 (EDSSPD2; 615349) by Nakajima et al. (2013), see 615291.0008.
In an Italian patient with spondylodysplastic Ehlers-Danlos syndrome-2 (EDSSPD2; 615349), Nakajima et al. (2013) identified compound heterozygosity for 2 mutations in the B3GALT6 gene: a c.16C-T transition resulting in an arg6-to-trp (R6W) substitution, and a 9-bp deletion (c.415_423del) resulting in a truncated protein (Met139Ala141del). Neither mutation was detected in more than 200 ethnicity matched controls or in public databases, including the 1000 Genomes Project database.
For discussion of the 9-bp deletion in the B3GALT6 gene (c.415_423del) that was found in compound heterozygous state in a patient with spondylodysplastic Ehlers-Danlos syndrome-2 (EDSSPD2; 615349) by Nakajima et al. (2013), see 615291.0010.
In affected members of 2 unrelated Iranian families with spondyloepimetaphyseal dysplasia with joint laxity type 1 with fractures (SEMDJL1; 271640), Malfait et al. (2013) identified a c.619G-C transversion in the B3GALT6 gene, resulting in an asp207-to-his (D207H) substitution at a highly conserved residue. In 1 family the mutation occurred in 2 sibs in homozygous state; in the other family it occurred in 2 sibs in compound heterozygous state with a 22-bp deletion in B3GALT6 (c.323_344del; 615291.0014), resulting in a frameshift (Ala108GlyfsTer163). Both mutations occurred within the predicted catalytic galactosyltransferase domain. The D207H substitution was not found in 106 control individuals or in the 1000 Genomes Project or NHLBI Exome Variant Server (ESP6500) databases.
In an Iranian patient with spondyloepimetaphyseal dysplasia with joint laxity type 1 with fractures (SEMDJL1; 271640), Malfait et al. (2013) identified homozygosity for a 649G-A transition in the B3GALT6 gene, resulting in a gly216-to-ser (G217S) substitution at a highly conserved residue in the catalytic galactosyltransferase domain. The mutation was not found in 106 control individuals or in the 1000 Genomes Project or NHLBI Exome Variant Server (ESP65000) databases.
For discussion of the 22-bp deletion in the B3GALT6 gene (c.323_344del) that was found in compound heterozygous state in patients with spondyloepimetaphyseal dysplasia with joint laxity type 1 with fractures (SEMDJL1; 271640) by Malfait et al. (2013), see 615291.0012.
In a boy, born of consanguineous Iranian parents (family VII), with spondylodysplastic Ehlers-Danlos syndrome-2 (EDSSPD2; 615349), Van Damme et al. (2018) identified homozygosity for a c.545A-G transition (c.545A-G, NM_080605.3) in the B3GALT6 gene, resulting in a tyr182-to-cys (Y182C) substitution at a conserved residue in the galactosyltransferase domain. The unaffected parents were heterozygous for the mutation, which was not present in the gnomAD database.
In an infant with Al-Gazali syndrome (ALGAZ; 609465), Sellars et al. (2014) identified compound heterozygous missense mutations in the B3GALT6 gene: ser159-to-tyr (S159Y) and glu265-to-asp (E265D; 615291.0017). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Ben-Mahmoud et al. (2018) stated that the nucleotide changes for these variants are c.476C-A (c.476C-A, NM080605.3) and c.795A-C, respectively.
For discussion of the glu265-to-asp (E265D) mutation in the B3GALT6 gene that was found in compound heterozygous state in an infant with Al-Gazali syndrome (ALGAZ; 609465) by Sellars et al. (2014), see 615291.0016. Ben-Mahmoud et al. (2018) stated that the nucleotide change for this variant is c.795A-C (c.795A-C, NM_080605.3).
In 1 of the Palestinian sibs with Al-Gazali syndrome (ALGAZ; 609465) reported by al-Gazali et al. (1999), Ben-Mahmoud et al. (2018) identified homozygosity for a c.618C-G transversion (c.618C-G, NM_080605.3) in the B3GALT6 gene, resulting in a cys206-to-trp (C206W) substitution at a highly conserved residue in the galactosyltransferase domain. The parents were heterozygous for the mutation. The variant was not present in the Exome Sequencing Project database. Expression of the variant in both HeLa and HEK-293 cells showed that it localized normally in the Golgi compartment. Examination of the effect of the variant on decorin processing in HeLa cells indicated impaired formation of immature decorin.
From a cohort of 40 families referred for genetic analysis because of suspicion of an inherited connective tissue disorder based primarily on joint and skin manifestations, Alazami et al. (2016) identified affected members of 3 families with a homozygous c.556T-C transition (c.556T-C, NM_080605.3) in the B3GALT6 gene, resulting in a phe186-to-leu (F186L) substitution. The probands in families 6 and 7 (12DG0715 and 12DG1291, respectively) presented with severe joint laxity, blue sclera, multiple joint dislocation, and recurrent fractures with severe osteopenia reminiscent of osteogenesis imperfecta. The proband in family 8 (12DG2397) presented in infancy with hip dislocation, joint laxity, and arthrogryposis. Maddirevula et al. (2018) identified another family (12DG1024) with a homozygous F186L mutation in the B3GALT6 gene. Based on a review of the clinical features of all of these patients, Maddirevula et al. (2018) diagnosed the patient in family 12DG2397 with spondylodysplastic type 2 Ehlers-Danlos syndrome (EDSSPD2; 615349), and the patients in the other 3 families with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1; 271640).
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Bai, X., Zhou, D., Brown, J. R., Crawford, B. E., Hennet, T., Esko, J. D. Biosynthesis of the linkage region of glycosaminoglycans: cloning and activity of galactosyltransferase II, the sixth member of the beta-1,3-galactosyltransferase family (beta-3-GalT6). J. Biol. Chem. 276: 48189-48195, 2001. [PubMed: 11551958] [Full Text: https://doi.org/10.1074/jbc.M107339200]
Ben-Mahmoud, A., Ben-Salem, S., Al-Sorkhy, M., John, A., Ali, B. R., Al-Gazali, L. A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the endoplasmic reticulum quality control in the mechanism of some beta-3-GalT6-pathy mutations. Clin. Genet. 93: 1148-1158, 2018. [PubMed: 29443383] [Full Text: https://doi.org/10.1111/cge.13236]
Maddirevula, S., Alsahli, S., Alhabeeb, L., Patel, N., Alzahrani, F., Shamseldin, H. E., Anazi, S., Ewida, N., Alsaif, H. S., Mohamed, J. Y., Alazami, A. M., Ibrahim, N., and 44 others. Expanding the phenome and variome of skeletal dysplasia. Genet. Med. 20: 1609-1616, 2018. [PubMed: 29620724] [Full Text: https://doi.org/10.1038/gim.2018.50]
Malfait, F., Kariminejad, A., Van Damme, T., Gauche, C., Syx, D., Merhi-Soussi, F., Gulberti, S., Symoens, S., Vanhauwaert, S., Willaert, A., Bozorgmehr, B., Kariminejad, M. H., Ebrahimiadib, N., Hausser, I., Huysseune, A., Fournel-Gigleux, S., De Paepe, A. Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder. Am. J. Hum. Genet. 92: 935-945, 2013. [PubMed: 23664118] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.016]
Nakajima, M., Mizumoto, S., Miyake, N., Kogawa, R., Iida, A., Ito, H., Kitoh, H., Hirayama, A., Mitsubuchi, H., Miyazaki, O., Kosaki, R., Horikawa, R., and 19 others. Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. Am. J. Hum. Genet. 92: 927-934, 2013. [PubMed: 23664117] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.003]
Sellars, E. A., Bosanko, K. A., Lepard, T., Garnica, A., Schaefer, G. B. A newborn with complex skeletal abnormalities, joint contractures, and bilateral corneal clouding with sclerocornea. Semin. Pediat. Neurol. 21: 84-87, 2014. [PubMed: 25149931] [Full Text: https://doi.org/10.1016/j.spen.2014.04.007]
Van Damme, T., Pang, X., Guillemyn, B., Gulberti, S., Syx, D., De Rycke, R., Kaye, O., de Die-Smulders, C. E. M., Pfundt, R., Kariminejad, A., Nampoothiri, S., and 10 others. Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome. Hum. Molec. Genet. 27: 3475-3487, 2018. [PubMed: 29931299] [Full Text: https://doi.org/10.1093/hmg/ddy234]
Zhou, D., Dinter, A., Gallego, R. G., Kamerling, J. P., Vliegenthart, J. F. G., Berger, E. G., Hennet, T. A beta-1,3-N-acetylglucosaminyltransferase with poly-N-acetyllactosamine synthase activity is structurally related to beta-1,3-galactosyltransferases. Proc. Nat. Acad. Sci. 96: 406-411, 1999. Note: Erratum: Proc. Nat. Acad. Sci. 97: 11673-11675, 2000. [PubMed: 9892646] [Full Text: https://doi.org/10.1073/pnas.96.2.406]