Identification of a novel gene causing frontotemporal lobar degeneration and amyotrophic lateral sclerosis through whole genome sequencing.

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are lethal neurodegenerative disorders; however an appropriate therapy is not available. They belong to the same spectrum of disorders, suggesting that they share overlapping disease mechanisms. Although several genes have been identified, these do not fully explain the genetic aetiology so that other genes remain to be identified. One such gene resides at chromosome 9p13-p21 (ALSFTD2 locus), causally linked in 13 FTLD-ALS families worldwide. We also have described an FTLD-ALS family (DR14) significantly linked to the ALSFTD2 locus in which all genes were excluded, suggesting that the genetic defect resides outside the known genes or is undetectable using standard techniques. We also obtained linkage with chromosome 14q31-q32, suggesting a major modifier gene. Here, we propose to identify the genetic defect in the ALSFTD2 locus and the modifier gene at chromosome 14q. We will determine the complete genome sequence of selected patients of DR14 and follow up identified genetic variants in the linked regions. This strategy will allow for the detection of simple and complex DNA variations, maximizing the chance of identifying the genes. Characterization of these genes will contribute to the understanding of disease mechanisms for FTLD, ALS and related disorders.

Keywords:GENE IDENTIFICATION, DEMENTIA, MOLECULAR GENOMICS, FRONTOTEMPORAL LOBAR DEGENERATION

Disciplines:Genetics, Systems biology, Molecular and cell biology