Analysis of IFT74as a candidate gene for chromosome 9p-linked ALS-FTD Academic Article uri icon

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abstract

  • BACKGROUND: A new locus for amyotrophic lateral sclerosis--frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p. METHODS: We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus. RESULTS: Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples. CONCLUSION: Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.

authors

  • Momeni, Parastoo
  • Schymick, Jennifer
  • Jain, Shushant
  • Cookson, Mark R
  • Cairns, Nigel J
  • Greggio, Elisa
  • Greenway, Matthew
  • Berger, Stephen
  • Pickering-Brown, Stuart
  • Chiò, Adriano
  • Fung, Hon Chung
  • Holtzman, David M
  • Huey, Edward D
  • Wassermann, Eric M
  • Adamson, Jennifer
  • Hutton, Michael L
  • Rogaeva, Ekaterina
  • St George-Hyslop, Peter
  • Rothstein, Jeffrey D
  • Hardiman, Orla
  • Grafman, Jordan
  • Singleton, Andrew
  • Hardy, John
  • Traynor, Bryan J

publication date

  • December 2006

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