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

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Author(s): Momeni Parastoo | Schymick Jennifer | Jain Shushant | Cookson Mark | Cairns Nigel | Greggio Elisa | Greenway Matthew | Berger Stephen | Pickering-Brown Stuart | Chiò Adriano | Fung Hon | Holtzman David | Huey Edward | Wassermann Eric | Adamson Jennifer | Hutton Michael | Rogaeva Ekaterina | St George-Hyslop Peter | Rothstein Jeffrey | Hardiman Orla | Grafman Jordan | Singleton Andrew | Hardy John | Traynor Bryan

Journal: BMC Neurology
ISSN 1471-2377

Volume: 6;
Issue: 1;
Start page: 44;
Date: 2006;
Original page

ABSTRACT
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.

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Tangokurs Rapperswil-Jona

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