SHC2 gene copy number in multiple system atrophy (MSA)
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Multiple system atrophy (MSA) is a sporadic, late onset, rapidly progressing neurodegenerative disorder, which is characterized by autonomic failure, together with Parkinsonian, cerebellar, and pyramidal motor symptoms. The pathologic hallmark is the glial cytoplasmic inclusion with α-synuclein aggregates. MSA is thus an α-synucleinopathy. Recently, Sasaki et al. reported that heterozygosity for copy number loss of Src homology 2 domain containing-transforming protein 2 (SHC2) genes (heterozygous SHC2 gene deletions) occurred in DNAs from many Japanese individuals with MSA. Because background copy number variation can be distinct in different human populations, we assessed SHC2 allele copy number in DNAs from a US cohort of individuals with MSA, to determine the contribution of SHC2 gene copy number variation in an American cohort followed at a US referral center for MSA. Our cohort included 105 carefully phenotyped individuals with MSA.
We studied 105 well-characterized patients with MSA and 5 control subjects with reduced SHC2 gene copy number. We used two TaqMan Gene Copy Number Assays, to determine the copy number of two segments of the SHC2 gene that are separated by 27 kb.
Assay results of DNAs from all of our 105 subjects with MSA showed 2 copies of both segments of their SHC2 genes.
Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds.
KeywordsMultiple system atrophy Genetics Copy number variation Movement disorders, SHC2
The investigators express appreciation to the many patients with multiple system atrophy who have participated in the research studies of the Vanderbilt Autonomic Dysfunction Center. The investigators would also like to thank Professor Sau W. Cheug, of the department of Molecular and Human Genetics at Baylor University. Supported by U54 NS065736 (DR), P01HL056693 (DR), R01HL071784 (DR), and UL1RR024975 (GB), all from the National Institutes of Health, Bethesda MD, USA. The Autonomic Diseases Consortium is a part of the NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided from the National Institute of Neurological Diseases and Stroke (NINDS) and the NIH Office of Rare Diseases Research (ORDR).The Autonomic Diseases Consortium includes Vanderbilt University, Mayo Clinic (Rochester), Beth Israel Hospital (Harvard), New York University, and the NINDS Intramural Program.
Conflict of interest
Dr. Ferguson receives research support from the NIH. Dr. Garland receives research support from the NIH. Dr. Hamid receives research support from the NIH, American Cancer Society, and Vanderbilt University. Dr. Phillips receives research support from the NIH, state of TN, BioMarin Pharmaceutical Inc; serves on the scientific advisory board for BioMarin Pharmaceutical Inc. Dr. Shibao receives research support from the NIH and American Heart Association. Dr. Raj receives research support from the NIH and provided expert testimony for a legal proceeding. Dr. Biaggioni receives research support from the NIH, served as editor of Primer on the Autonomic Nervous System. Dr. Robertson receives research support from the NIH, served as editor of Primer on the Autonomic Nervous System, editor of Clinical and Translation Science: Principles of Human Research, and served on the Merck Scientific Advisory Board.
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