SNCB P123H - GET-Evidence

Curation:
Currentness:

SNCB P123H

(SNCB Pro123His)


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Short summary

Reported by ClinVar to cause Lewy body dementia (https://www.ncbi.nlm.nih.gov/clinvar/variation/7026/). In ClinVar this variant is reported as “pathogenic” (causing this condition) by a single source, OMIM, which cites Ohtake et al 2004 (https://www.ncbi.nlm.nih.gov/pubmed/15365127).

Ohtake et al found this variant in one of 43 patients screened, and hypothesized it causes a “dominant trait with reduced penetrance or a risk factor polymorphism”. The statistical significance of this observation is unclear; this variant is moderately (but not extremely) rare: according to ExAC it is carried by roughly 1 in 1400 individuals (http://exac.broadinstitute.org/variant/5-176048219-G-T). There don’t appear to be any publications since 2004 that have studied affected patients and confirmed Ohtake et al’s hypothesis regarding this gene (SNCB) as a cause of this disease.

Variant evidence
Computational 2

NBLOSUM=3, conserved residue

See Ohtake H et al. 2004 (15365127), unpublished research (below).

Functional 3

Cell free assay, B103 cell lines, co-expression with SNCA

See Wei J et al. 2007 (17652097).

Case/Control

OR=5.5, p-value=0.15

See Ohtake H et al. 2004 (15365127).

Familial 1

LOD of 0.6 with low penetrance

See Ohtake H et al. 2004 (15365127).

 
Clinical importance
Severity 4

Early onset dementia and motor-skill impairment

See Ohtake H et al. 2004 (15365127), Mukaetova-Ladinska EB et al. 2006 (16297436), Wei J et al. 2007 (17652097).

Treatability 2

Treatments are still in the basic-research stage

See Ohtake H et al. 2004 (15365127), Wei J et al. 2007 (17652097).

Penetrance 3
 

Impact

Moderate clinical importance, Uncertain pathogenic

(The "moderate clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

dominant

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr5:176048219: 0.0% (2/10758) in EVS
  • Frequency shown in summary reports: 0.0% (2/10758)

Publications
 

Ohtake H, Limprasert P, Fan Y, Onodera O, Kakita A, Takahashi H, Bonner LT, Tsuang DW, Murray IV, Lee VM, Trojanowski JQ, Ishikawa A, Idezuka J, Murata M, Toda T, Bird TD, Leverenz JB, Tsuji S, La Spada AR. Beta-synuclein gene alterations in dementia with Lewy bodies. Neurology. 2004 Sep 14;63(5):805-11. PubMed PMID: 15365127; PubMed Central PMCID: PMC1808539.

In a screen of alpha-synuclein and beta-synuclein in 43 individuals with dementia with Lewy bodies, this variant was found in 1 kindred and not seen in 416 control chromosomes nor 45 sporadic Parkinson’s disease chromosomes (OR = 5.48, fisher p-value = 0.1575). This variant is conserved in rat, mouse and bovine. The index case, a Caucasian male, showed dementia onset at 61yo, motor decline at 73yo and death at 79yo. Brain tissue was used for neuropathological study and while diffuse SNCB immunoreactivity was present in a diffuse manner, it was not present in the aggregates or inclusions. A family pedigree

Mukaetova-Ladinska EB, McKeith IG. Pathophysiology of synuclein aggregation in Lewy body disease. Mech Ageing Dev. 2006 Feb;127(2):188-202. Epub 2005 Nov 16. Review. PubMed PMID: 16297436.

In this review, the authors point out that SNCB mutations are rare and have not been associated with AD Parkinson’s disease. SNCA mutations have more evidence pointing towards their toxicity.

Wei J, Fujita M, Nakai M, Waragai M, Watabe K, Akatsu H, Rockenstein E, Masliah E, Hashimoto M. Enhanced lysosomal pathology caused by beta-synuclein mutants linked to dementia with Lewy bodies. J Biol Chem. 2007 Sep 28;282(39):28904-14. Epub 2007 Jul 24. PubMed PMID: 17652097.

In a functional study, B103 neuroblastoma cells were stably transfected with the P123H mutation showed abundant formation of lysosomal inclusion bodies similar to the histopathology of lysosomal storage diseases. A cell-free system showed increase aggregation properties. The overexpression of SNCA greatly stimulated the formation of these inclusion bodies.

Genomes
 

Other external references
 

Other in silico analyses
 

  • NBLOSUM100 score = 5
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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