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Clinical Autonomic Research

, Volume 24, Issue 1, pp 25–30 | Cite as

SHC2 gene copy number in multiple system atrophy (MSA)

  • Marcus C. Ferguson
  • Emily M. Garland
  • Lora Hedges
  • Bethany Womack-Nunley
  • Rizwan Hamid
  • John A. PhillipsIII
  • Cyndya A. Shibao
  • Satish R. Raj
  • Italo Biaggioni
  • David Robertson
Research Article

Abstract

Purpose

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.

Methods

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.

Results

Assay results of DNAs from all of our 105 subjects with MSA showed 2 copies of both segments of their SHC2 genes.

Conclusion

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.

Keywords

Multiple system atrophy Genetics Copy number variation Movement disorders, SHC2 

Notes

Acknowledgments

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.

References

  1. 1.
    Breheny P, Chalise P, Batzler A, Wang L, Fridley BL (2012) Genetic association studies of copy-number variation: should assignment of copy number states precede testing? PLoS ONE 7:e34262CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Clayton-Smith J, Giblin C, Smith RA, Dunn C, Willatt L (2010) Familial 3q29 microdeletion syndrome providing further evidence of involvement of the 3q29 region in bipolar disorder. Clin Dysmorphol 19:128–132CrossRefPubMedGoogle Scholar
  3. 3.
    Combarros O, Infante J, Llorca J, Berciano J (2003) Interleukin-1A (-889) genetic polymorphism increases the risk of multiple system atrophy. Mov Disord 18:1385–1386CrossRefPubMedGoogle Scholar
  4. 4.
    Furiya Y, Hirano M, Kurumatani N, Nakamuro T, Matsumura R, Futamura N, Ueno S (2005) Alpha-1-Antichymotrypsin gene polymorphism and susceptibility to multiple system atrophy (MSA). Mol Brain Res 138:178–181CrossRefPubMedGoogle Scholar
  5. 5.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676CrossRefPubMedGoogle Scholar
  6. 6.
    Girirajan S, Eichler EE (2010) Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet 19:R176–R187CrossRefPubMedGoogle Scholar
  7. 7.
    Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciute D, Tate SK, Caboclo LO, Sander JW, Clayton L, Linney KN, Shianna KV, Gumbs CE, Smith J, Cronin KD, Maia JM, Doherty CP, Pandolfo M, Leppert D, Middleton LT, Gibson RA, Johnson MR, Matthews PM, Hosford D, Kalviainen R, Eriksson K, Kantanen AM, Dorn T, Hansen J, Kraemer G, Steinhoff BJ, Wieser HG, Zumsteg D, Ortega M, Wood NW, Huxley-Jones J, Mikati M, Gallentine WB, Husain AM, Buckley PG, Stallings RL, Podgoreanu MV, Delanty N, Sisodiya SM, Goldstein DB (2010) Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 86:707–718CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Infante J, Llorca J, Berciano J, Combarros O (2005) Interleukin-8, intercellular adhesion molecule-1 and tumour necrosis factor-alpha gene polymorphisms and the risk for multiple system atrophy. J Neurol Sci 228:11–13CrossRefPubMedGoogle Scholar
  9. 9.
    Ingason A, Rujescu D, Cichon S, Sigurdsson E, Sigmundsson T, Pietilainen O, Buizer-Voskamp J, Strengman E, Francks C, Muglia P, Gylfason A, Gustafsson O, Olason PI, Steinberg S, Hansen T, Jakobsen K, Rasmussen H, Giegling I, Moeller HJ, Hartmann A, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Bramon E, Kiemeney L, Franke B, Murray R, Vassos E, Toulopoulou T, Muehleisen T, Tosato S, Ruggeri M, Djurovic S, Andreassen O, Zhang Z, Werge T, Ophoff R, Rietschel M, Noethen M, Petursson H, Stefansson H, Peltonen L, Collier D, Stefansson K, St Clair DM (2011) Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry 16:17–25CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Mayo P, Hartshorne T, Li K, McMunn-Gibson C, Spencer K, Schnetz-Boutaud N (2001) CNV analysis using TaqMan Copy Number Assays. Current protocols in human genetics. John Wiley & Sons, Inc, TorontoGoogle Scholar
  11. 11.
    Nishimura M, Kawakami H, Komure O, Maruyama H, Morino H, Izumi Y, Nakamura S, Kaji R, Kuno S (2002) Contribution of the interleukin-1 beta gene polymorphism in multiple system atrophy. Mov Disord 17:808–811CrossRefPubMedGoogle Scholar
  12. 12.
    Nishimura M, Kuno S, Kaji R, Kawakami H (2005) Influence of a tumor necrosis factor gene polymorphism in Japanese patients with multiple system atrophy. Neurosci Lett 374:218–221CrossRefPubMedGoogle Scholar
  13. 13.
    Ozawa T (2006) Pathology and genetics of multiple system atrophy: an approach to determining genetic susceptibility spectrum. Acta Neuropathol 112:531–538CrossRefPubMedGoogle Scholar
  14. 14.
    Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy–Drager syndrome). J Neurol Sci 94:79–100CrossRefPubMedGoogle Scholar
  15. 15.
    Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23:41–46CrossRefPubMedGoogle Scholar
  16. 16.
    Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews T, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444:444–454CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Sasaki H, Emi M, Iijima H, Ito N, Sato H, Yabe I, Kato T, Utsumi J, Matsubara K (2011) Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy. Mol Brain 4:24CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R, Gibbs JR, Simon-Sanchez J, Paisan-Ruiz C, Bras J, Ding J, Chen H, Traynor BJ, Arepalli S, Zonozi RR, Revesz T, Holton J, Wood N, Lees A, Oertel W, Wullner U, Goldwurm S, Pellecchia MT, Illig T, Riess O, Fernandez HH, Rodriguez RL, Okun MS, Poewe W, Wenning GK, Hardy JA, Singleton AB, Del SF, Schneider S, Bhatia KP, Gasser T (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65:610–614CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaeki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam T, Ye K, Wigler M (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, Sasaki H (2008) Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 Genes. Mov Disord 23:1161–1167CrossRefPubMedGoogle Scholar
  21. 21.
    Stemberger S, Scholz SW, Singleton AB, Wenning GK (2011) Genetic players in multiple system atrophy: unfolding the nature of the beast. Neurobiol Aging 32:1924.e5–1924.e14CrossRefGoogle Scholar
  22. 22.
    Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182CrossRefPubMedGoogle Scholar
  23. 23.
    Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246CrossRefPubMedGoogle Scholar
  24. 24.
    Zoghbi HY, Warren ST (2010) Neurogenetics: advancing the “Next-Generation” of brain research. Neuron 68:165–173CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    The Multiple-System Atropohy Research Collaboration (2013) Mutations in COQ2 in familial multiple system atrophy. N Engl J Med 369:233–244CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Marcus C. Ferguson
    • 1
  • Emily M. Garland
    • 1
  • Lora Hedges
    • 4
    • 5
  • Bethany Womack-Nunley
    • 4
    • 5
  • Rizwan Hamid
    • 4
    • 5
  • John A. PhillipsIII
    • 4
    • 5
  • Cyndya A. Shibao
    • 1
  • Satish R. Raj
    • 1
  • Italo Biaggioni
    • 1
    • 2
  • David Robertson
    • 1
    • 2
    • 3
  1. 1.Autonomic Dysfunction Center, Department of MedicineVanderbilt UniversityNashvilleUSA
  2. 2.Department of PharmacologyVanderbilt UniversityNashvilleUSA
  3. 3.Department of NeurologyVanderbilt UniversityNashvilleUSA
  4. 4.Department of PediatricsVanderbilt UniversityNashvilleUSA
  5. 5.Department of GeneticsVanderbilt UniversityNashvilleUSA

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