GGGGCC Repeat in C9ORF72 ID'd As Genetic Cause of ALS

Repeat expansion in C9ORF72 causes chromosome 9p21-linked ALS, frontotemporal dementia

THURSDAY, Sept. 22 (HealthDay News) -- The GGGGCC hexanucleotide repeat expansion in the non-coding region of C9ORF72 gene on chromosome 9p21 is the most common genetic abnormality in familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in a large FTD/ALS kindred; and, it is the underlying cause of a considerable proportion of familial and sporadic ALS in a Finnish population, according to two studies published online Sept. 21 in Neuron.

Mariely DeJesus-Hernandez, from the Mayo Clinic Florida in Jacksonville, and colleagues reported an expansion of a non-coding GGGGCC hexanucleotide repeat in C9ORF72 in a large FTD/ALS kindred. The C9ORF72 repeat expansion was the most common genetic abnormality found in 11.7 and 22.5 percent of familial FTD and ALS, respectively. The repeat expansion led to formation of nuclear RNA foci, and to loss of one alternatively spliced C9ORF72 transcript.

Alan E. Renton, from the National Institutes of Health in Bethesda, Md., and colleagues investigated C9ORF72 in the ALS-FTD locus of chromosome 9p21 in a Finnish population. A large hexanucleotide (GGGGCC) repeat expansion was identified in the first intron of C9ORF72 on the affected haplotype, which segregates with disease in the study population. This repeat expansion was the underlying cause of 46.0 and 21.1 percent of familial and sporadic ALS, respectively. Combined with the D90A SOD1 mutation, this monogenic cause is responsible for 87 percent of familial ALS in Finland. One-third of familial ALS cases of outbred European descent also had this repeat expansion, making it the most common genetic cause of ALS-FTD.

"A massive hexanucleotide repeat expansion within C9ORF72 is the cause of chromosome 9p21-linked ALS, FTD, and ALS-FTD," Renton and colleagues write.

One authors from the second study disclosed financial ties to Microsoft Research.

Abstract - DeJesus-Hernandez
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Abstract - Renton
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