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Ancient origin of the CAG expansion causing Huntington disease in a Spanish population

Javier García-Planells1, Juan A Burguera, Pilar Solís

  • 1Laboratory of Genetics and Medicine, Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain.

Human Mutation
|April 16, 2005
PubMed

Insights

Huntington disease (HD) genetic history in Valencia suggests the primary mutation originated 4,700-10,000 years ago. Local founder effects influenced the CAG expansion

Area of Science:

  • Genetics
  • Neurodegenerative Disorders
  • Population Genetics

Background:

  • Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the huntingtin gene.
  • The origin and spread of the HD mutation are thought to stem from a limited number of mutational events.
  • Understanding the genetic history of HD is crucial for comprehending its global distribution and disease mechanisms.

Purpose of the Study:

  • To investigate the genetic history and origin of the Huntington disease (HD) mutation in the Valencian population of Eastern Spain.
  • To analyze the specific haplotypes associated with the HD mutation in this region.
  • To estimate the age of the CAG expansion and identify potential founder effects.

Main Methods:

  • Haplotype analysis of the HD/CCG repeat and flanking short tandem repeats (STRs) in 83 family probands.
  • Segregation analysis and PHASE program for phase-known mutant chromosomes.
  • Construction of extended haplotypes using STRs D4S106 and D4S3034.

Main Results:

  • At least two main chromosomes associated with the HD mutation were identified in the Valencian population: one with allele 7 and another with allele 10.
  • Haplotype A-7-A (H1) was the predominant haplotype, found in a large majority of mutant chromosomes analyzed.
  • The CAG expansion associated with H1 was estimated to be between 4,700 and 10,000 years old.
  • A non-homogenous distribution of extended haplotypes suggested local founder effects.

Conclusions:

  • The Huntington disease (HD) mutation in the Valencian population is primarily associated with a specific ancestral haplotype (H1).
  • The estimated age of the CAG expansion points to an ancient origin, potentially predating the establishment of distinct regional populations.
  • Evidence of local founder effects indicates that demographic events have shaped the distribution of HD haplotypes within the region.

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