Article

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.

Download full-text

Full-text

Available from: Mark Cookson, Jul 17, 2015
0 Followers
 · 
197 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34-74 years) and disease duration (mean = 5.3, range = 1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with M(r) 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.
    Brain 03/2012; 135(Pt 3):709-22. DOI:10.1093/brain/awr354 · 10.23 Impact Factor
  • Source
    • "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 . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal dementia (FTD) is the second major cause of dementia in persons below the age of 65 years after Alzheimer disease. FTD is clinically, pathologically, and genetically heterogeneous and has been associated with mutations in different genes located on chromosomes 17, 9, and 3. In our study we report a novel heterozygous g.26218G>A variant in exon 6 of charged multivesicular body protein 2B (CHMP2B), predicted to cause the amino acid change p.Ser187Asn, in one patient diagnosed with FTD. We were not able to determine the mode of inheritance of the mutation as we did not have access to the genetically informative family members of the proband; those who were screened did not carry the variant. We did not find this variant in 273 White controls although we did find it in 6 of 94 African-American controls. Most of the mutations in CHMP2B which are considered pathogenic lead to partial deletion of the C-terminus region of CHMP2B protein. Based on previous reports and on our current data, missense mutations in this gene seem unlikely to be pathogenic. The pathogenicity of CHMP2B mutations requires further investigation.
    Alzheimer disease and associated disorders 06/2010; DOI:10.1097/WAD.0b013e3181df20c7 · 2.69 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P=0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P=0.022), the USA (OR 1.4 95% CI 1.02-1.92, P=0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97-2.17, P=0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72-1.37, P=0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43.
    Neurobiology of aging 03/2009; 30(4):656-65. DOI:10.1016/j.neurobiolaging.2009.01.009 · 4.85 Impact Factor
Show more