# Genetic mechanism of conserved ancestral haplotype in SCA10

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $159,132

## Abstract

PROJECT SUMMARY/ABSTRACT
Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of
(ATTCT)n repeat in intron 9 of the ATXN10 gene. SCA10 exists exclusively in Latin American (LA)
populations of Native American Ancestry and East Asian (EA) populations. All our SCA10 patients share a
single haplotype that includes the G allele at rs41524745. The G allele has the minor allele frequency of 2-
4% in EA and LA populations but 0% elsewhere. These data suggest that the single ancestral mutation has
risen on the G(+) haplotype in EA 15,000-20,000 years ago before peopling Americas. Although the
distance between rs41524547 and the SCA10 repeat is long enough for multiple historical recombination
events in normal populations, our SCA10 population shows no dissociation of the G allele from the SCA10
expansion. Furthermore, the G allele is located adjacent to the seed sequence of miR4762-5p. We obtained
G(+) DNA from the 1000 Genomes repository and our own general population samples and tested for
SCA10 expansions. We found up to 25% of these samples show SCA10 repeat expansions. Our studies
further suggest that SCA10 expansions interrupted by (ATTCC)n or (ATCCT)n(ATCCC)n repeat are fully
penetrant while pure (ATTCT)n expansions show reduced penetrance. Based on these observations we
propose to test following hypotheses: (1) the G allele at rs41524547 predisposes the SCA10 repeat for
pure (ATTCT)n repeat expansion (Type A expansion), that remains mostly non-penetrant, and (2) the
(ATTCT)n-(ATTCC)n (Type B) or (ATTCT)n-(ATCCT)n-(ATCCC)n (Type C) repeat insertion into Type A
expansion drives the SCA10 pathogenicity. To test these hypotheses we will aim to:
Aim 1) Determine the relationship between SCA10 expansions and the G allele at rs41524547:
 (1a) Case-control study to document the tight association of SCA10 expansion with the G(+) haplotype.
 (1b) Determine repeat structures in SCA10 patients and other G(+) individuals.
Aim 2) Confirm that Type B and Type C, but not Type A, expansions are fully pathogenic.
 (2a) Characterize phenotypes of transgenic mice expressing each of Types A, B and C expansion.
 (2b) Determine phenotype of Purkinje-like cells (PC) derived from iPS cells of SCA10 patients with Types
 A, B and C expansions.
 (2c) Establish penetrance rates of Type A, B and C expansions in SCA10 sibships ≥50 years of age.
 (2d) Obtain cross-sectional clinical data from SCA10 family members with Types A, B and C expansions.
Aim 3) Determine if the G allele at rs41524547 reduces downstream recombination rates, protects
against the toxicity of SCA10 RNA expansions, or promote expanded states of the SCA10 repeat:
 (3a) Determine the recombination rate in the rs41524547-SCA10 interval in sperm from SCA10 patients.
 (3b) Determine the effect of G-to-C genome editing at rs41524547 in iPSC-derived SCA10 PC.

## Key facts

- **NIH application ID:** 9890198
- **Project number:** 1R01NS115002-01
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** TETSUO ASHIZAWA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $159,132
- **Award type:** 1
- **Project period:** 2019-02-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890198

## Citation

> US National Institutes of Health, RePORTER application 9890198, Genetic mechanism of conserved ancestral haplotype in SCA10 (1R01NS115002-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9890198. Licensed CC0.

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