HGNC Approved Gene Symbol: SNCB
SNOMEDCT: 312991009, 80098002; ICD10CM: G31.83; ICD9CM: 331.82;
Cytogenetic location: 5q35.2 Genomic coordinates (GRCh38): 5:176,620,082-176,630,534 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.2 | Dementia, Lewy body | 127750 | Autosomal dominant | 3 |
Jakes et al. (1994) examined the composition of proteins found in Alzheimer disease (104300) neurofibrillary lesions. They identified 2 abundant proteins, both with apparent molecular weights of 19 kD. One was alpha-synuclein (SNCA; 163890). Cloning and sequencing revealed that the other was a novel 134-amino acid protein, which they named beta-synuclein. The sequences of the 2 proteins are 61% identical, establishing the existence of a family of human brain synucleins. Northern blotting detected a strong 1.3-kb signal in adult human brain. Weak hybridization was observed in skeletal muscle. Immunohistochemical localization showed that beta-synuclein is concentrated in presynaptic nerve terminals.
Lavedan et al. (1998) found that the SNCB gene contains 5 coding exons and at least one 5-prime untranslated exon, with intron-exon junctions similar to those of alpha-synuclein.
Spillantini et al. (1995) used PCR panels and fluorescence in situ hybridization to map the SNCB gene to human chromosome 5q35.
Spillantini et al. (1997) found no staining of beta-synuclein in Lewy bodies associated with Parkinson disease (168600). Consistent with this, Lavedan et al. (1998) found no evidence of linkage to SNCB in the probands of 71 families with apparent autosomal dominant Parkinson disease drawn from the various ethnic backgrounds.
Hashimoto et al. (2001) found that mice doubly transgenic for human alpha- and beta-synuclein had decreased accumulation of alpha-synuclein-immunoreactive neuronal inclusions and less severe neurodegenerative alterations compared to mice singly transgenic for human alpha-synuclein. In vitro cell culture studies showed that beta-synuclein coimmunoprecipitated with alpha-synuclein and that cells transfected with beta-synuclein were resistant to alpha-synuclein accumulation. The findings suggested that beta-synuclein may be a natural negative regulator of alpha-synuclein aggregation.
Hashimoto et al. (2004) found that cultured neurons overexpressing beta-synuclein had increased Akt (164730) signaling activity and were resistant to neurotoxic effects of the pesticide rotenone compared to cells overexpressing alpha-synuclein and control cells. Downregulation of Akt activity using Akt siRNA resulted in increased susceptibility to the neurotoxic effects of rotenone. Coimmunoprecipitation studies suggested a direct molecular interaction between beta-synuclein and Akt.
In 2 unrelated patients with dementia with Lewy bodies (127750), 1 of whom had a family history of the disorder, Ohtake et al. (2004) identified 2 different heterozygous mutations in the SNCB gene (602569.0001; 602569.0002). Ohtake et al. (2004) postulated that an alteration in SNCB may impair its normal inhibitory action on the formation of toxic alpha-synuclein fibrils, thereby indirectly contributing to disease pathogenesis.
In a sporadic case of dementia with Lewy bodies (127750), Ohtake et al. (2004) identified a heterozygous 208G-A transition in exon 4 of the SNCB gene, resulting in a val70-to-met (V70M) substitution in a highly conserved residue. As valine is a branched- chain amino acid and methionine is linear with a bulky sulfur group, the change may affect the tertiary structure of the protein. The substitution was not identified in over 660 control chromosomes.
In a patient with dementia with Lewy bodies (127750) confirmed by neuropathologic examination, Ohtake et al. (2004) identified a heterozygous 368C-A transversion in exon 5 of the SNCB gene, resulting in a pro123-to-his (P123H) substitution in a highly conserved residue. A deceased sister and maternal uncle were affected, although molecular analysis was not performed. A first cousin, who was possibly affected, also carried the P123H mutation. The substitution was not identified in over 660 control chromosomes. Neuropathologic examination showed extensive Lewy body pathology in regions of the hippocampus, amygdala, and substantia nigra; there were no SNCB-immunoreactive aggregates.
Hashimoto, M., Bar-on, P., Ho, G., Takenouchi, T., Rockenstein, E., Crews, L., Masliah, E. Beta-synuclein regulates Akt activity in neuronal cells: a possible mechanism for neuroprotection in Parkinson's disease. J. Biol. Chem. 279: 23622-23629, 2004. [PubMed: 15026413] [Full Text: https://doi.org/10.1074/jbc.M313784200]
Hashimoto, M., Rockenstein, E., Mante, M., Mallory, M., Masliah, E. Beta-synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32: 213-223, 2001. [PubMed: 11683992] [Full Text: https://doi.org/10.1016/s0896-6273(01)00462-7]
Jakes, R., Spillantini, M. G., Goedert, M. Identification of two distinct synucleins from human brain. FEBS Lett. 345: 27-32, 1994. [PubMed: 8194594] [Full Text: https://doi.org/10.1016/0014-5793(94)00395-5]
Lavedan, C., Buchholtz, S., Auburger, G., Albin, R. L., Athanassiadou, A., Blancato, J., Burguera, J. A., Ferrell, R. E., Kostic, V., Leroy, E., Leube, B., Mota-Vieira, L., and 9 others. Absence of mutation in the beta- and gamma-synuclein genes in familial autosomal dominant Parkinson's disease. DNA Res. 5: 401-402, 1998. [PubMed: 10048491] [Full Text: https://doi.org/10.1093/dnares/5.6.401]
Lavedan, C., Leroy, E., Torres, R., Dehejia, A., Dutra, A., Buchholtz, S., Nussbaum, R. L., Polymeropoulos, M. H. Genomic organization and expression of the human beta-synuclein gene (SNCB) Genomics 54: 173-175, 1998. [PubMed: 9806846] [Full Text: https://doi.org/10.1006/geno.1998.5556]
Ohtake, H., Limprasert, P., Fan, Y., Onodera, O., Kakita, A., Takahashi, H., Bonner, L. T., Tsuang, D. W., Murray, I. V. J., Lee, V. M.-Y., Trojanowski, J. Q., Ishikawa, A., Idezuka, J., Murata, M., Toda, T., Bird, T. D., Leverenz, J. B., Tsuji, S., La Spada, A. R. Beta-synuclein gene alterations in dementia with Lewy bodies. Neurology 63: 805-811, 2004. [PubMed: 15365127] [Full Text: https://doi.org/10.1212/01.wnl.0000139870.14385.3c]
Spillantini, M. G., Divane, A., Goedert, M. Assignment of human alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes 4q21 and 5q35. Genomics 27: 379-381, 1995. [PubMed: 7558013] [Full Text: https://doi.org/10.1006/geno.1995.1063]
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., Goedert, M. Alpha-synuclein in Lewy bodies. Nature 388: 839-840, 1997. [PubMed: 9278044] [Full Text: https://doi.org/10.1038/42166]