This analysis identified 29 ALS risk loci, 22 of which were new. That number seemed low to Desikan. Indeed, a recent paper reported slower axonal transport in neurons derived from healthy MAPTH1 carriers Beevers et al. To dissect potential effects of the shared SNPs, the authors looked for expression quantitative trait loci that associated with them. These distinct effects on expression, and the separate inheritance of the two SNPs, suggest two independent risk factors residing in the same C9ORF72 locus.
BNIP1 encodes a protein that appears to block apoptotic suppressors and helps maintain the endoplasmic reticulum network. One study reports that it binds to the mitochondrial ubiquitin ligase RNF Tang et al. However, the human nervous system does not seem to express RNF, and the functional consequences of its binding to BNIP1 are unexplored. Geriatr Gerontol Int. Kamada M, et al. Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation.
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Optineurin mutations in patients with sporadic amyotrophic lateral sclerosis in China. Amyotroph Lateral Sclerosis Frontotemporal Degeneration. Pottier C, et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease.
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ALS, Frontotemporal Dementia Have Distinct Patterns of Brain Inflammation, Study Shows
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Genetics Tie ALS into the Frontotemporal Dementia Spectrum | ALZFORUM
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Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. Kunita R, et al. Otomo A. None of these 4 genes contained mutations in exons or 50 base pairs past intron or exon junctions that could be causative. The 3 families studied are relatively large from an ALS standpoint. Considering that 2 separate teams recently reported families also mapping to chromosome 9p, this locus may have a significant effect on ALS and FTD research.
Bearing in mind that a rapidly growing number of families are reported to have linkage to the chromosome 9p locus, it is increasingly plausible that a single gene is responsible for the joint occurrence of the 2 diseases rather than 2 separate genes with independent mutations. It is likely that additional medium-sized families with ALS or FTD will also map to this locus and aid in the reduction of what is still a sizeable region. A promising gene lies within this reduced candidate interval, namely, the TEK gene.
This is based on its similarity to the vascular endothelial growth factor VEGF gene. Other genes in the newly defined 9p locus will be further prioritized for mutation screening by sequencing in our 3 new families with ALS, FTD, or both, particularly those genes expressed in the brain. Finding the mutation and the responsible gene would have a substantial effect on understanding the etiology of these 2 diseases. Correspondence: Guy A.
Author Contributions: Study concept and design : Valdmanis and Rouleau. Analysis and interpretation of data : Valdmanis, Dupre, and Rouleau. Drafting of the manuscript : Valdmanis. Critical revision of the manuscript for important intellectual content : Dupre, Bouchard, Camu, Salachas, Meininger, Strong, and Rouleau.
Original Contribution. Paul N. Rouleau, MD, PhD. Family data. Gene and locus exclusion. Back to top Article Information. Sign in to access your subscriptions Sign in to your personal account.
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