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

Momeni P, Schymick J, Jain S, Cookson MR, Cairns NJ, Greggio E, Greenway MJ, Berger S, Pickering-Brown S, ChiĆ² 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 - BMC Neurol (2006)

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD, USA. momeni@mail.nih.gov <momeni@mail.nih.gov>

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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Family 476, 95, 549 and 13 originate from North America. WT indicates a mutation-negative subject, Q342X, G58D and I55L indicate subjects carrying a heterozygous sequence variation. Currently unaffected mutation carriers have not been shown; in all instances these individuals have not yet reached the maximum age at onset observed.
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Figure 4: Family 476, 95, 549 and 13 originate from North America. WT indicates a mutation-negative subject, Q342X, G58D and I55L indicate subjects carrying a heterozygous sequence variation. Currently unaffected mutation carriers have not been shown; in all instances these individuals have not yet reached the maximum age at onset observed.

Mentions: In the course of sequencing the intraflagellar transport gene (IFT74), we identified a C to T sequence variant at nucleotide 1024 in exon 13 in the proband of F476 (III-3, figures 4a and 5). This base pair change predicts a premature stop codon at position 342 of the peptide (Q342X) truncating the last 258 residues. This variant segregated with disease within the family as it was present in the two brothers of the proband diagnosed with ALS-FTD (III-1, III-4). The Q342X sequence variant was not present in four unaffected individuals within the kindred (II-3, III-2, IV-2 & IV-4), in 1,000 chromosomes from North American controls or in 900 chromosomes from the Human Genome Diversity Panel although this C to T base pair change is ostensibly in a library clone derived from human thymus (BX436367, clone CS0CAP001YM04, Life Technologies, Inc). One younger unaffected individual carried the Q342X sequence variant. We did not find IFT74 sequence variants in F2 by sequencing or exonic gene dosage methods (data not shown). Neither F476 or F2 had additional mutations in the other 13 genes within the 9p locus defined by the Dutch, Scandinavian and North American families[14-16] or in 47 additional genes in the larger haplotype.


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

Momeni P, Schymick J, Jain S, Cookson MR, Cairns NJ, Greggio E, Greenway MJ, Berger S, Pickering-Brown S, ChiĆ² 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 - BMC Neurol (2006)

Family 476, 95, 549 and 13 originate from North America. WT indicates a mutation-negative subject, Q342X, G58D and I55L indicate subjects carrying a heterozygous sequence variation. Currently unaffected mutation carriers have not been shown; in all instances these individuals have not yet reached the maximum age at onset observed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1764752&req=5

Figure 4: Family 476, 95, 549 and 13 originate from North America. WT indicates a mutation-negative subject, Q342X, G58D and I55L indicate subjects carrying a heterozygous sequence variation. Currently unaffected mutation carriers have not been shown; in all instances these individuals have not yet reached the maximum age at onset observed.
Mentions: In the course of sequencing the intraflagellar transport gene (IFT74), we identified a C to T sequence variant at nucleotide 1024 in exon 13 in the proband of F476 (III-3, figures 4a and 5). This base pair change predicts a premature stop codon at position 342 of the peptide (Q342X) truncating the last 258 residues. This variant segregated with disease within the family as it was present in the two brothers of the proband diagnosed with ALS-FTD (III-1, III-4). The Q342X sequence variant was not present in four unaffected individuals within the kindred (II-3, III-2, IV-2 & IV-4), in 1,000 chromosomes from North American controls or in 900 chromosomes from the Human Genome Diversity Panel although this C to T base pair change is ostensibly in a library clone derived from human thymus (BX436367, clone CS0CAP001YM04, Life Technologies, Inc). One younger unaffected individual carried the Q342X sequence variant. We did not find IFT74 sequence variants in F2 by sequencing or exonic gene dosage methods (data not shown). Neither F476 or F2 had additional mutations in the other 13 genes within the 9p locus defined by the Dutch, Scandinavian and North American families[14-16] or in 47 additional genes in the larger haplotype.

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD, USA. momeni@mail.nih.gov <momeni@mail.nih.gov>

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.

Show MeSH
Related in: MedlinePlus