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

Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD, USA. <>
BMC Neurology (Impact Factor: 2.49). 02/2006; 6:44. DOI: 10.1186/1471-2377-6-44
Source: PubMed

ABSTRACT 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.

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Available from: Mark Cookson, Jul 17, 2015
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    • "However, a number of families have been reported with an autosomal dominant pattern of disease in which affected members may develop either FTD or ALS or both (FTD–ALS). Several of these families have shown genetic linkage to a region on chromosome 9p21, with the combined data defining a minimum linkage region of 3.7 Mb, containing only five known genes (Momeni et al., 2006; Morita et al., 2006; Vance et al., 2006; Valdmanis et al., 2007; Luty et al., 2008; Le Ber et al., 2009; Gijselinck et al., 2010; Boxer et al., 2011; Pearson et al., 2011). Importantly, the same chromosomal region has been identified in several large independent genome-wide association studies of both ALS and FTD, implicating the genetic defect at chromosome 9p in sporadic forms of both diseases (van Es et al., 2009; Laaksovirta et al., 2010; Shatunov et al., 2010; van Deerlin et al., 2010). "
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    • "This mutation was not found in 273 Caucasian neurologically normal controls (NDPT 098, NDPT 099, and NDPT 096: Coriell Cell Repositories, Camden, NJ, USA). In Momeni et al., 2006, 400 neurological normal controls were sequenced for CHMP2B exon 6 and this variant was not found in those samples 12 . "
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    • "Immunohistological analysis of UBAP1 in a case of familial FTLD(Momeni et al., 2006). UBAP1 positive neuronal cytoplasmic inclusions (arrows) in (a) frontal cortex and (b) hippocampus. "
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