Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

摘要: Background Frontotemporal lobar degeneration (FTLD) is a neurodegenerative brain disorder that can be accompanied by signs of amyotrophic lateral sclerosis (ALS). Objective To identify novel gene for FTLD-ALS. Design Genome-wide linkage study in multiplex family with FTLD-ALS subsequent fine mapping and mutation analyses. Setting Memory Clinic the Middelheim General Hospital. Patients An extended Belgian autosomal dominant FTLD-ALS, DR14, mean age at onset 58.1 years (range, 51-65 [n = 9]) disease duration 6.4 1-17 [n = 9]). The proband clinical FTLD showed typical pathology neuronal ubiquitin-immunoreactive inclusions were positive transactivation response DNA-binding protein 43 (TDP-43). Main Outcome Measure Linkage to chromosome 9 14. Results We found significant 9p23-q21 (multipoint logarithm odds [LOD] score = 3.38) overlapping known locus ( ALSFTD2 ) nearly second 14q31-q32 LOD score = 2.79). Obligate meiotic recombinants defined candidate regions 74.7 megabase pairs (Mb) 14.6 Mb near telomere 14q. In both loci, haplotype segregated all patients family. Mutation analysis selected genes copy number variation loci did not reveal segregating pathogenic mutations. Conclusions Family DR14 provides additional evidence importance reveals possible identification underlying genetic defect(s) will significantly contribute understanding mechanisms FTLD, ALS, associated disorders.