Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD

• Published in: BMC neurology Vol. 6; no. 1; p. 44
• Main Authors: Momeni, Parastoo, Schymick, Jennifer, Jain, Shushant, Cookson, Mark R, Cairns, Nigel J, Greggio, Elisa, Greenway, Matthew J, 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.12.2006; BioMed Central; BMC
• Subjects: Amyotrophic Lateral Sclerosis - complications; Amyotrophic Lateral Sclerosis - epidemiology; Amyotrophic Lateral Sclerosis - genetics; Base Sequence; Chromosome Aberrations - statistics & numerical data; Chromosome Mapping; Chromosomes, Human, Pair 9 - genetics; Dementia - complications; Dementia - epidemiology; Dementia - genetics; Genetic Predisposition to Disease - epidemiology; Genetic Predisposition to Disease - genetics; Heterozygote; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; North America; Polymorphism, Single Nucleotide - genetics; Prevalence; Risk Assessment - methods; Risk Factors; North America
• ISSN: 1471-2377; 1471-2377
• DOI: 10.1186/1471-2377-6-44

A new locus for amyotrophic lateral sclerosis--frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p. 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. 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. Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.