Spinocerebellar degenerations are neurodegenerative diseases which involve the cerebellum and its connections and affect as many individuals in the US as multiple sclerosis. Among the hereditary forms, the dominant spinocerebellar ataxis (SCAs) represent clinically and genetically complex disorders leading to severe ataxia, oculo-motor abnormalities and variable degrees of motor disturbance and neuropathy. The genetic defect for SCA type 2 has been localized to chromosome (CHR) 12. Marked anticipation in a large pedigree with SCA2 has recently been documented suggesting that SCA2-like SCA2 and SCA3 - is caused by expansion of a DNA trinucleotide repeat (TNR). A unique resource of four SCA2 families with greater than 500 affected individuals, genetic markers and physical mapping tools has been established by our group and used to narrow the SCA2 region to approximately 1cM genetically and less than 1 Mb physically. A YAC contig including the flanking markers AFM240we1 and AFM291xe9 has been constructed and a contig of P1 artificial chromosome (PAC) clones is being developed. Using these resources, four specific aims are proposed with the goal to isolate and characterize the SCA2 gene: 1) the SCA2 region will be further narrowed using a panel of meiotic breakpoints on disease chromosomes and novel microsatellite markers. These will be generated as part of aim 2. 2) The existing contigs of YAC and PAC clones will be expanded to provide a detailed physical map of the SCA2 region. Contigs will b e used to saturate the candidate region with di- and trinucleotide repeats. 3) Candidate SCA2 genes will be identified by evaluating trinucleotide repeats for expansion by cDNA selection, and by exon amplification. Mutations in each of the SCA2 families will be evaluated by Southern blot, SSCP and repeat expansion analysis. 4) SCA2 transcript(s) and protein(s) will be characterized to determine cellular and tissue distribution and embryonic expression using Northern blotting, reverse-transcribed PCR, in situ hybridization, Western blotting and immunocytochemistry. Identification of the SCA2 gene will enhance classification of ataxias and permit presymptomatic diagnosis. It will also contribute to our knowledge of mechanisms underlying late-onset neuronal degeneration.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Mammalian Genetics Study Section (MGN)
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Spinella, Giovanna M
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Cedars-Sinai Medical Center
Los Angeles
United States
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Figueroa, Karla P; Gan, Shi-Rui; Perlman, Susan et al. (2018) C9orf72 repeat expansions as genetic modifiers for depression in spinocerebellar ataxias. Mov Disord 33:497-498
Scoles, Daniel R; Pulst, Stefan M (2018) Spinocerebellar Ataxia Type 2. Adv Exp Med Biol 1049:175-195
Scoles, Daniel R; Meera, Pratap; Schneider, Matthew D et al. (2017) Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 544:362-366
Meera, Pratap; Pulst, Stefan; Otis, Thomas (2017) A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2. Elife 6:
Pflieger, Lance T; Dansithong, Warunee; Paul, Sharan et al. (2017) Gene co-expression network analysis for identifying modules and functionally enriched pathways in SCA2. Hum Mol Genet 26:3069-3080
Graf, Julia; Hellenbroich, Yorck; Veelken, Norbert et al. (2016) Two different genetic diseases in the same patient: Coincident, concomitant, or causally related? Mov Disord 31:491-2
Scoles, Daniel R; Ho, Mi H T; Dansithong, Warunee et al. (2015) Repeat Associated Non-AUG Translation (RAN Translation) Dependent on Sequence Downstream of the ATXN2 CAG Repeat. PLoS One 10:e0128769
Dansithong, Warunee; Paul, Sharan; Figueroa, Karla P et al. (2015) Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model. PLoS Genet 11:e1005182
Matilla-DueƱas, A; Ashizawa, T; Brice, A et al. (2014) Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias. Cerebellum 13:269-302
Neuenschwander, Annalese G; Thai, Khanh K; Figueroa, Karla P et al. (2014) Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis. JAMA Neurol 71:1529-34

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