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
Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD, USA.
BMC Neurol. 2006 Dec 13;6:44. 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.
肌萎缩侧索硬化症-额颞叶痴呆（ALS-FTD）的一个新基因座最近被定位于9号染色体短臂。
我们在两个ALS-FTD家系（F476和F2）中确定了9号染色体短臂上的分离单倍型，并对该基因座内的候选基因进行了突变筛查。
该基因座的候选基因测序显示，家系476（F476）的鞭毛内运输蛋白74（IFT74）基因存在一个与疾病相关的截短突变（Q342X），但在2号家系（F2）的IFT74基因中未检测到突变。虽然这两个家系都不足以明确表明IFT74突变是9号染色体连锁的ALS-FTD的病因，还是排除其作为病因的可能性，但在F476中观察到的突变性质（预计会使蛋白质截短258个氨基酸）促使我们对大量ALS和FTD病例（n = 420）的该基因开放阅读框进行测序。在一例散发性语义性痴呆病例中发现了另一个序列变异（G58D）。在另外三名无关的患病个体中发现了I55L序列变异，但在800份人类多样性基因面板样本中的一名个体中也发现了该变异。
要确认IFT74序列变异的致病性，需要对其他9号染色体短臂连锁的家系进行筛查。
