Amyotrophic Lateral Sclerosis, Base Sequence, Chromosome Aberrations, Chromosome Mapping, Chromosomes, Human, Pair 9, Dementia, Genetic Predisposition to Disease, Heterozygote, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, North America, Polymorphism, Single Nucleotide, Prevalence, Risk Assessment, Risk Factors
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.
Medicine and Health Sciences | Neurology
Momeni P, Schymick J, Jain S, Cookson MR, Cairns NJ, Greggio E, Greenway MJ, Berger S, Pickering-Brown S, Chiò A, Fung HC, Holtzman DM, Huey ED, Wassermann EM, Adamson J, Hutton ML, Rogaeva E, St George-Hyslop P, Rothstein JD, Hardiman O, Grafman J, Singleton A, Hardy J, Traynor BJ. Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD. BMC Neurol. 2006 Dec;6:44.
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