Alternative titles; symbols
HGNC Approved Gene Symbol: B4GALNT1
SNOMEDCT: 726607007;
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38): 12:57,623,409-57,633,201 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | Spastic paraplegia 26, autosomal recessive | 609195 | Autosomal recessive | 3 |
The B4GALNT1 gene encodes beta-1,4-N-acetylgalactosaminyl transferase-1 (EC 2.4.1.92), an enzyme involved in the biosynthesis of complex gangliosides (G), which are mono- (M), di- (D), and tri- (T) sialic acid-containing glycosphingolipids generated by sequential glycosylations. Gangliosides are part of the larger family of glycosphingolipids and are components of the synaptic plasma membrane involved in synaptic plasticity, signal transduction, and endocytosis and then are critical for central nervous system development. B4GALNT1 catalyzes the transfer of N-acetylgalactosamine into GM3, GD3, and globotriaosylceramide by a beta-1,4 linkage (summary by Boukhris et al., 2013).
Nagata et al. (1992) used expression cloning to isolate the cDNA for beta-1,4-N-acetylgalactosaminyltransferase (GalNAcT), or G(M2)/G(D2) synthase. The cDNA encodes a 561-amino acid polypeptide. Northern blot analysis revealed that the gene is expressed as 2 differently sized transcripts in all cells tested that expressed G(MS), G(D2), or both. These findings indicate that the cDNAs catalyze the transfer of GalNAc into G(M3) and G(D3) by a beta-1,4 linkage, resulting in the synthesis of G(M2) and G(D2), respectively.
Furukawa et al. (1996) examined the genomic structure of the human GalNAcT gene and found that it contains more than 11 exons spanning over 8 kb of genomic DNA. They reported that the gene has at least 3 distinct transcription initiation sites that may be involved in cell type-specific gene expression.
By FISH, Furukawa et al. (1996) mapped the GALGT gene to 12q13.3. Hamlin et al. (1998) mapped the GALGT and KIF5A (602821) genes to 12q13 by FISH. They found that these genes are contained within the same approximately 200-kb YAC insert as the GLI (165220) and DDIT3 (126337) genes.
By exome sequencing of 5 families with autosomal recessive spastic paraplegia-26 (SPG26; 609195), Boukhris et al. (2013) identified 5 different homozygous mutations in the B4GALNT1 gene. The mutations segregated with the disorder in the families and were not found in large control databases. Subsequent analysis of this gene identified pathogenic mutations in 2 of 65 additional probands with a similar disorder. All mutations were truncating, except for 2 missense mutations that occurred at highly conserved residues (see, e.g., 601873.0001-601873.0005). No functional studies were performed. The phenotype was characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients had upper limb involvement. Additional features included intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder was slowly progressive.
Takamiya et al. (1996) found that mice with a disrupted B4galnt1 gene lacked all complex gangliosides, but did did not show any major histologic defects in their nervous systems or in gross behavior. Electrophysiologic studies showed a slight reduction in the neural conduction velocity from the tibial nerve to the somatosensory cortex, but not to the lumbar spine. The findings suggested that complex gangliosides are required in neuronal functions, such as synaptic transmission, but not in the morphogenesis and organogenesis of the brain. Higher levels of GM3 and GD3 expressed in the brains of these mutant mice may have been able to compensate for the lack of complex gangliosides.
Niemann-Pick disease type C (NPC; 257220) is a progressive neurodegenerative disorder caused by mutations in the NPC1 gene (607623) and characterized by intracellular accumulation of cholesterol and sphingolipids. To determine the relative contribution of ganglioside accumulation in the neuropathogenesis of Niemann-Pick C disease, Liu et al. (2000) bred NPC model mice with mice carrying a targeted mutation in GalNAcT. Unlike the NPC model mice, the double mutant mice did not exhibit central nervous system accumulation of gangliosides GM2 or of glycolipids GA1 and GA2. Histologic analysis revealed that the characteristic neuronal storage pathology of NPC disease was substantially reduced in the double mutant mice. By contrast, visceral pathology was similar in the NPC and double mutant mice. Most notably, the clinical phenotype of the double mutant mice, in the absence of CNS ganglioside accumulation and associated neuronal pathology, did not improve. The authors concluded that complex ganglioside storage, while responsible for much of the neuronal pathology, did not significantly influence the clinical phenotype of the NPC model.
In 3 Spanish sibs, born of consanguineous parents, with autosomal recessive spastic paraplegia-26 (SPG26; 609195), Boukhris et al. (2013) identified a homozygous 1-bp deletion (c.395delC) in the B4GALNT1 gene, resulting in a frameshift and premature termination (Pro132GlnfsTer7). The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not present in several large control databases.
In 2 Brazilian sibs with SPG26 (609195), Boukhris et al. (2013) identified a homozygous c.682C-T transition in the B4GALNT1 gene, resulting in an arg228-to-ter (R228X) substitution. The mutation, which was found by exome sequencing, was not present in several large control databases or in 2 unaffected sibs. Three additional sibs were reportedly affected.
In an Algerian patient, born of consanguineous parents, with SPG26 (609195), Boukhris et al. (2013) identified a homozygous 1-bp duplication (c.263dupG), resulting in a frameshift and premature termination (Leu89ProfsTer13). No other family members were available for study.
In 4 members of a Portuguese family with SPG26 (609195), Boukhris et al. (2013) identified a homozygous c.358C-T transition in the B4GALNT1 gene, resulting in a gln120-to-ter (Q120X) substitution. The mutation, which was found by exome sequencing and was not present in several large control databases, segregated with the disorder in the family.
In 3 German sibs with SPG26 (609195), Boukhris et al. (2013) identified a homozygous c.1298A-C transversion in the B4GALNT1 gene, resulting in an asp433-to-ala (D433A) substitution at a highly conserved residue. The mutation, which was found by exome sequencing, was not found in several large control databases and segregated with the disorder.
Boukhris, A., Schule, R., Loureiro, J. L., Lourenco, C. M., Mundwiller, E., Gonzalez, M. A., Charles, P., Gauthier, J., Rekik, I., Acosta Lebrigio, R. F., Gaussen, M., Speziani, F., and 21 others. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am. J. Hum. Genet. 93: 118-123, 2013. [PubMed: 23746551] [Full Text: https://doi.org/10.1016/j.ajhg.2013.05.006]
Furukawa, K., Soejima, H., Niikawa, N., Shiku, H., Furukawa, K. Genomic organization and chromosomal assignment of the human beta-1,4-N-acetylgalactosaminyltransferase gene. J. Biol. Chem. 271: 20836-20844, 1996. [PubMed: 8702839] [Full Text: https://doi.org/10.1074/jbc.271.34.20836]
Hamlin, P. J., Jones, P. F., Leek, J. P., Bransfield, K., Lench, N. J., Aldersley, M. A., Howdle, P. D., Markham, A. F., Robinson, P. A. Assignment of GALGT encoding beta-1,4N-acetylgalactosaminyl-transferase (GalNAc-T) and KIF5A encoding neuronal kinesin (D12S1889) to human chromosome band 12q13 by assignment to ICI YAC 26EG10 and in situ hybridization. Cytogenet. Cell Genet. 82: 267-268, 1998. [PubMed: 9858832] [Full Text: https://doi.org/10.1159/000015115]
Liu, Y., Wu, Y.-P., Wada, R., Neufeld, E. B., Mullin, K. A., Howard, A. C., Pentchev, P. G., Vanier, M. T., Suzuki, K., Proia, R. L. Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse. Hum. Molec. Genet. 9: 1087-1092, 2000. [PubMed: 10767333] [Full Text: https://doi.org/10.1093/hmg/9.7.1087]
Nagata, Y., Yamashiro, S., Yodoi, J., Lloyd, K. O., Shiku, H., Furukawa, K. Expression cloning of beta-1,4-N-acetylgalactosaminyltransferase cDNAs that determine the expression of G(M2) and G(D2) gangliosides. J. Biol. Chem. 267: 12082-12089, 1992. Note: Erratum: J. Biol. Chem. 269: 7045 only, 1994. [PubMed: 1601877]
Takamiya, K., Yamamoto, A., Furukawa, K., Yamashiro, S., Shin, M., Okada, M., Fukumoto, S., Haraguchi, M., Takeda, N., Fujimura, K., Sakae, M., Kishikawa, M., Shiku, H., Furukawa, K., Aizawa, S. Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc. Nat. Acad. Sci. 93: 10662-10667, 1996. [PubMed: 8855236] [Full Text: https://doi.org/10.1073/pnas.93.20.10662]