title: Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort.
abstract: BACKGROUND
  Spinocerebellar ataxia type 1 (SCA1) is a late onset autosomal dominant cerebellar ataxia, caused by CAG triplet repeat expansion in the ATXN1 gene. The frequency of SCA1 occurrence is more in Southern India than in other regions as observed from hospital-based studies. However there are no reports on variability of CAG repeat expansion, phenotype-genotype association and founder mutations in a homogenous population from India.
  
  
  METHODS
  Genomic DNA isolated from buccal mouthwash of the individuals in the cohort was used for PCR-based diagnosis of SCA1. Subsequently SNP's found within the ATXN1 loci were identified by Taqman allelic discrimination assays. Significance testing of the genotype-phenotype associations was calculated by Kruskal-Wallis ANOVA test with post-hoc Dunnett's test and Pearson's correlation coefficient.
  
  
  RESULTS
  By genetic analysis of an affected population in Southern India we identified 21 pre-symptomatic individuals including four that were well past the average age of disease onset of 44 years, 16 symptomatic and 63 normal individuals. All pre-symptomatic cases harbor "pure" expansions of greater than 40 CAGs. Genotyping to test for the presence of two previously identified SNPs showed a founder effect of the same repeat carrying allele as in the general Indian population. We show that SCA1 disease onset is significantly delayed when transmission of the disease is maternal.
  
  
  CONCLUSIONS
  Our finding of early disease onset in individuals with a paternally inherited allele could serve as valuable information for clinicians towards early detection of SCA1 in patients with affected fathers. Identification of older pre-symptomatic individuals (n = 4) in our cohort among individuals with a shared genetic and environmental background, suggests that second site genetic or epigenetic modifiers might significantly affect SCA1 disease progression. Moreover, such undetected SCA1 cases could underscore the true prevalence of SCA1 in India.
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, Karnataka, India. dhanyak@ncbs.res.in.|Manipal University, Manipal, 576104, India. dhanyak@ncbs.res.in.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Kumaran
authors.affiliation: Department of Neurological Sciences, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. krishnan.balagopal@gmail.com.
authors.forename: Krishnan
authors.initials: K
authors.lastname: Balagopal
authors.affiliation: Department of Community Health, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. dralex98@cmcvellore.ac.in.
authors.forename: Reginald George Alex
authors.initials: RG
authors.lastname: Tharmaraj
authors.affiliation: Department of Neurological Sciences, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. drsanjith@yahoo.co.in.
authors.forename: Sanjith
authors.initials: S
authors.lastname: Aaron
authors.affiliation: Department of Community Health, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. kurien@cmcvellore.ac.in.
authors.forename: Kuryan
authors.initials: K
authors.lastname: George
authors.affiliation: Department of Community Health, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. jpmuliyil@gmail.com.
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Muliyil
authors.affiliation: Department of Neurological Sciences, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. ajithsivadasan@yahoo.com.
authors.forename: Ajith
authors.initials: A
authors.lastname: Sivadasan
authors.affiliation: Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. sdanda@cmcvellore.ac.in.
authors.forename: Sumita
authors.initials: S
authors.lastname: Danda
authors.affiliation: Department of Neurological Sciences, Christian Medical College and Hospital, Vellore, Tamil Nadu, India. mathewalex@cmcvellore.ac.in.
authors.forename: Mathew
authors.initials: M
authors.lastname: Alexander
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, Karnataka, India. gaiti@ncbs.res.in.
authors.forename: Gaiti
authors.initials: G
authors.lastname: Hasan
mesh_terms: D000328:Adult; D017668:Age of Onset; D000067696:Ataxin-1; D000067528:Ataxins; D015331:Cohort Studies; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins