HGNC Approved Gene Symbol: GM2A
SNOMEDCT: 71253000;
Cytogenetic location: 5q33.1 Genomic coordinates (GRCh38) : 5:151,253,185-151,270,440 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q33.1 | GM2-gangliosidosis, AB variant | 272750 | Autosomal recessive | 3 |
The GM2 activator is a low molecular weight, soluble protein that binds to the GM2 ganglioside, extracts it from the membrane, and solubilizes it as an activator/lipid complex which forms the substrate for the GM2 degradation by beta-hexosaminidase A (Klima et al., 1991).
Using probes corresponding to the amino acid sequence of purified mature human GM2A, Schroder et al. (1989) cloned GM2A from a fibroblast cDNA library. The cDNA, which appeared to be incomplete at its 5-prime end, encodes a deduced 179-amino acid protein that includes a mature peptide of 160 amino acids. Schroder et al. (1989) also observed a minor form of GM2A lacking 2 N-terminal serine residues.
Furst et al. (1990) purified mature GM2A from postmortem human kidney. The 162-amino acid protein has an extended hydrophobic segment from amino acids 15 to 90 that may form a triple-helical lipid-binding cavity. It has an N-linked carbohydrate chain at asn32.
Using a partial GM2A clone to screen a cDNA library prepared from fibroblasts cultured from a patient with a juvenile form of Sandhoff disease (268800), followed by anchored PCR to obtain the 5-prime sequence, Klima et al. (1991) cloned 2 GM2A splice variants. The variants differ only at their 3-prime UTR, which is very long in both cases, and encode an identical 194-amino acid protein.
Crystal Structure
Wright et al. (2000) determined the crystal structure of GM2 activator at 2.0-angstrom resolution, which revealed a previously unobserved fold whose main feature is an 8-stranded cup-shaped antiparallel beta-pleated sheet. They stated that the striking feature of the GM2A structure is an accessible central hydrophobic cavity rather than a buried hydrophobic core. They suggested that the mouth of the beta-cup, which contains flexible surface loops and a short alpha-helix, may control lipid entry to the cavity.
Using an enzyme-linked immunoadsorbant assay (ELISA) to identify the the GM2 activator protein in human-mouse somatic cell hybrids, Burg et al. (1985) assigned the GM2A gene to chromosome 5. On the other hand, Kleyn et al. (1991) concluded from somatic cell hybrid studies that the gene does not map to chromosome 5. Xie et al. (1992) resolved the controversy concerning the chromosomal localization of the GM2A gene. They demonstrated that confusion had been caused by the presence of a previously unidentified processed GM2A pseudogene on chromosome 3. Furthermore, by use of a human/hamster somatic hybrid cell panel, they confirmed the location of the functional GM2A gene on chromosome 5. They concluded that GM2A should be considered a possible candidate for the site of the mutation in some forms of spinal muscular atrophy that map to 5q. By fluorescence in situ hybridization, Heng et al. (1993) regionalized the GM2A gene to 5q31.3-q33.1; thus, it is not a candidate gene for spinal muscular atrophy (SMA; 253300), which had been mapped to 5q11.2-q13.3.
Swallow et al. (1993) used PCR analysis of somatic cell hybrids and in situ hybridization to map the GM2A gene to 5q32-q33. They also confirmed the assignment of a pseudogene GM2AP to chromosome 3.
Yamanaka et al. (1994) mapped the mouse Gm2a gene to chromosome 11.
Klima et al. (1991) determined that the GM2A gene contains at least 4 exons and spans over 9.5 kb.
In patients with AB variant GM2-gangliosidosis (272750), Schroder et al. (1991) identified homozygous mutations in the GM2A gene (613109.0001-613109.0002).
By RT-PCR of the GM2A gene in a patient with deficiency of GM2-activator protein, Chen et al. (1999) detected some normal-sized cDNA and a smaller cDNA species, which was not seen in the RT-PCR products from normal controls. Sequencing revealed that although the patient's normal-sized cDNA contained a single nonsense mutation in exon 2, his smaller cDNA was the result of an in-frame deletion of exon 2. Long PCR was used to amplify introns 1 and 2 from the patient and normal genomic DNA, and no differences in size, in 5-prime and 3-prime end sequences, or in restriction-mapping patterns were observed. From these data, Chen et al. (1999) developed a set of 4 PCR primers that could be used to identify GM2A mutations. With this procedure, they demonstrated that the patient was probably homozygous for a glu54-to-ter nonsense mutation (613109.0005). Chen et al. (1999) pointed to the work of Dietz et al. (1993) and of others, indicating that shortened reading frames (i.e., early stop codons) can lead not only to mRNA instability, but also to the in-frame skipping of the constitutive exon in which the mutation is found.
Liu et al. (1997) generated mice with a disrupted Gm2a gene as a model; knockout mouse models for Tay-Sachs and Sandhoff disease had previously been studied. Mice with disruption of the Hexa gene (the Tay-Sachs disease model) were asymptomatic, whereas those with absence of Hexb (the Sandhoff disease model) were severely affected. The mice with disruption of Gm2a demonstrated neuronal storage, but only in restricted regions of the brain, reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in these mice consisted of GM2 with a low amount of GA2. Their results demonstrated that the activator protein is required for GM2 degradation and also may indicate a role for GM2 activator in GA2 degradation.
In cultured fibroblasts derived from a black female infant, born of unrelated parents, with immunologically proven GM2 activator protein deficiency (272750), who was reported by de Baecque et al. (1975), Schroder et al. (1991) identified a homozygous 412T-C transition (counted from A of the initiation codon) in the GM2A gene, resulting in a cys107-to-arg (C107R) substitution in the mature protein. In cells from the same patient, Xie et al. (1992) found the same mutation, which resulted in a cys138-to-arg (C138R) substitution in a different numbering system. Expression studies of the mutant supported the view that the point mutation was responsible for the disease phenotype. (Mahuran (1994) pointed out that the mutations identified by Schroder et al. (1991) (CYS107ARG) and Xie et al. (1992) (CYS138ARG) are the same but derived from different amino acid numbering systems.)
In an infant with variant AB of GM2-gangliosidosis (272750), Schroder et al. (1993) identified a 506G-C transversion in the GM2A gene, resulting in substitution of proline for arginine-169 (R169P). The patient was homozygous, whereas both parents were heterozygous. Other studies suggested that the R169P mutation resulted in premature degradation of the mutant GM2 activator, either during the posttranslational processing steps or after reaching the lysosome. With other mutations, the phenotype appears to be due to inactivation of the physiologic activator function.
In a Saudi Arabian child with the AB variant of GM2-gangliosidosis (272750), the offspring of consanguineous parents, Schepers et al. (1996) identified homozygosity for a 3-bp deletion, AAG (nucleotides 262-264), resulting in deletion of lys88. The earliest sign of GM2A deficiency was a mild motor weakness beginning at 8 months of age. By 12 months of age, psychomotor retardation and hypotonia, associated with poor head control, hyporeflexia, and failure to sit unsupported were noted. After 14 months of age, the patient developed generalized convulsions, infantile spasms, and decreased visual attentiveness. Hyperacusis was evident and a cherry red spot on the macula was observed. The disease progressed rapidly after 24 months of age, associated with progressive deterioration, lateral nystagmus, hepatomegaly, encephalomegaly, and brain atrophy. Activities of beta-hexosaminidases A and B in leukocytes and plasma were normal.
In the offspring of a consanguineous Spanish mating with GM2-gangliosidosis AB variant (272750), Schepers et al. (1996) identified homozygosity for a single-base deletion at codon 137 (410A) that caused a frameshift in the GM2A gene. The frameshift resulted in substitution of 33 amino acids, the loss of another 24 amino acid residues, and a termination codon at residue 170. Although the cultured fibroblasts of both patients reported by Schepers et al. (1996) produced normal levels of GM2A mRNA, they lacked a lysosomal form of GM2A protein. Pulsed-chase labeling of cultured fibroblasts indicated premature degradation of both the mutant and the truncated GM2A protein in the endoplasmic reticulum or Golgi. These results were supported by in vitro translation experiments and expression of the mutated proteins.
Chen et al. (1999) studied a Laotian child with the AB variant form of GM2-gangliosidosis (272750) and identified a 160G-T transversion in the GM2A gene, resulting in a glu54-to-ter (E54X) substitution.
In 3 patients from a highly consanguineous Saudi Arabian family with the AB variant form of GM2-gangliosidosis (272750), Salih et al. (2015) identified a homozygous c.164C-T transition (c.164C-T, ENST00000357164) in the GM2A gene, resulting in a pro55-to-leu (P55L) substitution at a highly conserved residue in the MD-2-related lipid-recognition domain. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was found at a very low frequency in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
Burg, J., Conzelmann, E., Sandhoff, K., Solomon, E., Swallow, D. M. Mapping of the gene coding for the human GM2 activator protein to chromosome 5. Ann. Hum. Genet. 49: 41-45, 1985. [PubMed: 3865618] [Full Text: https://doi.org/10.1111/j.1469-1809.1985.tb01674.x]
Chen, B., Rigat, B., Curry, C., Mahuran, D. J. Structure of the GM2A gene: identification of an exon 2 nonsense mutation and a naturally occurring transcript with an in-frame deletion of exon 2. Am. J. Hum. Genet. 65: 77-87, 1999. [PubMed: 10364519] [Full Text: https://doi.org/10.1086/302463]
de Baecque, C. M., Suzuki, K., Rapin, I., Johnson, A. B., Whethers, D. L., Suzuki, K. GM2-gangliosidosis, AB variant: clinico-pathological study of a case. Acta Neuropath. (Berlin) 33: 207-226, 1975.
Dietz, H. C., Valle, D., Francomano, C. A., Kendzior, R. J., Jr., Pyeritz, R. E., Cutting, G. R. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259: 680-683, 1993. [PubMed: 8430317] [Full Text: https://doi.org/10.1126/science.8430317]
Furst, W., Schubert, J., Machleidt, W., Meyer, H. E., Sandhoff, K. The complete amino-acid sequences of human ganglioside GM2 activator protein and cerebroside sulfate activator protein. Europ. J. Biochem. 192: 709-714, 1990. [PubMed: 2209618] [Full Text: https://doi.org/10.1111/j.1432-1033.1990.tb19280.x]
Hechtman, P., Gordon, B. A., Ng Ying Kin, N. M. K. Deficiency of the hexosaminidase A activator protein in a case of GM2 gangliosidosis; variant AB. Pediat. Res. 16: 217-222, 1982. [PubMed: 6801612] [Full Text: https://doi.org/10.1203/00006450-198203000-00011]
Heng, H. H. Q., Xie, B., Shi, X.-M., Tsui, L.-C., Mahuran, D. J. Refined mapping of the GM2 activator protein (GM2A) locus to 5q31.3-q33.1, distal to the spinal muscular atrophy locus. Genomics 18: 429-431, 1993. [PubMed: 8288250] [Full Text: https://doi.org/10.1006/geno.1993.1491]
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Li, Y.-T., Muhiudeen, I. A., DeGasperi, R., Hirabayashi, Y., Li, S.-C. Presence of activator proteins for the enzymic hydrolysis of GM1 and GM2 gangliosides in normal human urine. Am. J. Hum. Genet. 35: 629-634, 1983. [PubMed: 6881139]
Liu, Y., Hoffmann, A., Grinberg, A., Westphal, H., McDonald, M. P., Miller, K. M., Crawley, J. N., Sandhoff, K., Suzuki, K., Proia, R. L. Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment. Proc. Nat. Acad. Sci. 94: 8138-8143, 1997. [PubMed: 9223328] [Full Text: https://doi.org/10.1073/pnas.94.15.8138]
Mahuran, D. J. Personal Communication. Toronto, Ontario, Canada 12/1/1994.
Salih, M. A., Seidahmed, M. Z., El Khashab, H. Y., Hamad, M. H. A., Bosley, T. M., Burn, S., Myers, A., Landsverk, M. L., Crotwell, P. L., Bilguvar, K., Mane, S., Kruer, M. C. Mutation in GM2A leads to a progressive chorea-dementia syndrome. Tremor Other Hyperkinet. Mov. (N.Y.) 5: 306, 2015. Note: Electronic Article. [PubMed: 26203402] [Full Text: https://doi.org/10.7916/D8D21WQ0]
Schepers, U., Glombitza, G., Lemm, T., Hoffmann, A., Chabas, A., Ozand, P., Sandhoff, K. Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am. J. Hum. Genet. 59: 1048-1056, 1996. [PubMed: 8900233]
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Swallow, D. M., Islam, I., Fox, M. F., Povey, S., Klima, H., Schepers, U., Sandhoff, K. Regional localization of the gene coding for the GM2 activator protein (GM2A) to chromosome 5q32-33 and confirmation of the assignment of GM2AP to chromosome 3. Ann. Hum. Genet. 57: 187-193, 1993. [PubMed: 8257088] [Full Text: https://doi.org/10.1111/j.1469-1809.1993.tb01594.x]
Wright, C. S., Li, S.-C., Rastinejad, F. Crystal structure of human GM2-activator protein with a novel beta-cup topology. J. Molec. Biol. 304: 411-422, 2000. [PubMed: 11090283] [Full Text: https://doi.org/10.1006/jmbi.2000.4225]
Xie, B., Kennedy, J. L., McInnes, B., Auger, D., Mahuran, D. Identification of a processed pseudogene related to the functional gene encoding the G-M2 activator protein: localization of the pseudogene to human chromosome 3 and the functional gene to human chromosome 5. Genomics 14: 796-798, 1992. [PubMed: 1427911] [Full Text: https://doi.org/10.1016/s0888-7543(05)80190-9]
Xie, B., Wang, W., Mahuran, D. J. A cys138-to-arg substitution in the G-M2 activator protein is associated with the AB variant form of G-M2 gangliosidosis. Am. J. Hum. Genet. 50: 1046-1052, 1992. [PubMed: 1570834]
Yamanaka, S., Johnson, O. N., Lyu, M. S., Kozak, C. A., Proia, R. L. The mouse gene encoding the G(M2) activator protein (Gm2a): cDNA sequence, expression, and chromosome mapping. Genomics 24: 601-604, 1994. [PubMed: 7713516] [Full Text: https://doi.org/10.1006/geno.1994.1674]