To determine the genetic basis of familial frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS) we performed a clinical and genetic analysis of an affected family. A 51-year-old man with behavioral variant FTLD with ALS had a family history of the disease suggestive of autosomal dominant inheritance with incomplete penetrance. Genetic studies in this patient demonstrated the presence of an amplified hexanucleotide repeat (>30) polymorphism in the chromosome 9 open reading frame 72 (C9ORF72) gene which was previously identified as a cause of FTLD. Five others unaffected from the family were negative (all had less than 11 repeats). Because of the clinical and pathological overlap between FTLD and AD we performed a larger genome-wide association study and did not find association of single nucleotide polymorphisms (SNPs) in the C9ORF72 gene with Alzheimer’s disease (AD) risk. Bioinformatic analysis of C9ORF72 using the Gene Expression Omnibus database showed expression differences in patients with muscular dystrophy, neural tube defects, and schizophrenia. We also report analysis of gene expression in brain regions using the Allen Human Brain Atlas. Defects in this recently reported gene are now believed to be the most common cause of inherited ALS and an important cause of inherited FTLD. Our work suggests that the gene may also be important in other neurological and psychiatric conditions.
Keywords: dementia, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, motor neuron disease, ubiquitin, disinhibition, hexanucleotide repeat
Citation: Friedland RP, Shah JJ, Farrer LA, Vardarajan B, Rebolledo-Mendez JD, Mok K and Hardy J (2012) Behavioral variant frontotemporal lobar degeneration with amyotrophic lateral sclerosis with a chromosome 9p21 hexanucleotide repeat. Front. Neur. 3:136. doi: 10.3389/fneur.2012.00136
Received: 17 July 2012; Accepted: 08 September 2012;
Published online: 04 October 2012.
Edited by:Peter Kochunov, Texas Biomedical Research Institute, USA
Reviewed by:Jun Zhang, Texas Tech University Health Sciences Center, USA
Copyright: © 2012 Friedland, Shah, Farrer, Vardarajan, Rebolledo-Mendez, Mok and Hardy. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Robert P. Friedland, School of Medicine, University of Louisville, HSC Building A Room 120, 500 South Preston Street, Louisville, KY 40292, USA. e-mail: firstname.lastname@example.org