Mutations in ERBB4 That Disrupt The NRG-ErbB4 Pathway Cause Autosomal Dominant Familial ALS Type 19 (P1.083)

2014 
OBJECTIVE: To identify a novel causative gene for FALS. BACKGROUND: Identification of novel causative genes for familial ALS (FALS) is a challenging task because of small family sizes and incomplete penetrance. Recent development of massively parallel sequencing method has allowed us to identify causative genes in these situations. DESIGN/METHODS: DNA samples from a Japanese FALS pedigree were obtained with informed consent. Linkage analysis was conducted with the assumption of autosomal-dominant mode of inheritance. Whole genome sequencing (WGS) was conducted on the proband, an affected sibling and the unaffected mother using a GAII Illumina Genome Analyzer. Novel non-synonymous variants were screened using DNA samples from 477 normal controls. Additional 364 FALS pedigrees and 818 SALS patients were included in mutational analysis. Functional studies were conducted using COS-7 cells expressing wild-type or mutant ErbB4. RESULTS: WGS revealed 382, 404 and 411 novel non-synonymous variants in the three individuals. Linkage analysis assuming complete penetrance revealed 3 candidate loci with the maximum LOD score of 1.8, where no novel non-synonymous variants were identified. Assuming incomplete penetrance (penetrance = 0.8), additional 7 loci were obtained with the LOD score >0.8, where only the variant c. 2780 G>A (p. R927Q) in ERBB4 was not identified in controls. Mutational analysis in additional samples revealed the same mutation in a Canadian pedigree and a de novo mutation c. 3823C.>T (p.R1275W) in a Japanese SALS patient. Clinical presentations of patients with mutations were those of typical ALS diagnosed as definite or probable ALS. Functional analysis revealed decreased level of autophosphorylation upon stimulation by NRG-1. CONCLUSIONS: This study revealed that mutations in ERBB4 that disrupt the NRG-ErbB4 pathway cause autosomal dominant ALS (ALS19). This study provides a new insight into ALS pathogenesis and paves a way for development of innovative therapeutic strategies such as upregulating ErbB4 functions using NRGs or their agonists. Study Supported by: KAKENHI, the Global COE Program and a Grant-in-Aid [H23-Jitsuyoka (Nanbyo)-Ippan-004]. Disclosure: Dr. Takahashi has nothing to disclose. Dr. Fukuda has nothing to disclose. Dr. Yoshimura has nothing to disclose. Dr. Toyoda has nothing to disclose. Dr. Kurppa has nothing to disclose. Dr. Moritoyo has nothing to disclose. Dr. Belzil has nothing to disclose. Dr. Elenius has nothing to disclose. Dr. Rouleau has nothing to disclose. Dr. Fujiyama has nothing to disclose. Dr. Morishita has nothing to disclose. Dr. Goto has nothing to disclose. Dr. Tsuji has nothing to disclose.
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