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


CONCLUSIONS
Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.
Momeni
Parastoo
P
Laboratory of Neurogenetics, National Institute of Aging, NIH, Bethesda, MD, USA. momeni@mail.nih.gov <momeni@mail.nih.gov>
Schymick
Jennifer
J
Jain
Shushant
S
Cookson
Mark R
MR
Cairns
Nigel J
NJ
Greggio
Elisa
E
Greenway
Matthew J
MJ
Berger
Stephen
S
Pickering-Brown
Stuart
S
Chiò
Adriano
A
Fung
Hon Chung
HC
Holtzman
David M
DM
Huey
Edward D
ED
Wassermann
Eric M
EM
Adamson
Jennifer
J
Hutton
Michael L
ML
Rogaeva
Ekaterina
E
St George-Hyslop
Peter
P
Rothstein
Jeffrey D
JD
Hardiman
Orla
O
Grafman
Jordan
J
Singleton
Andrew
A
Hardy
John
J
Traynor
Bryan J
BJ
D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D001483:Base Sequence; D002869:Chromosome Aberrations / Q000706:statistics & numerical data; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003704:Dementia / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009656:North America; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors