Identification and characterization of novel ERBB4 variant associated with sporadic amyotrophic lateral sclerosis (ALS)

초록

Amyotrophic Lateral Sclerosis (ALS) is the most common type of motor neuron disease characterized by progressive motor neuron degeneration in brain and spinal cord. Most cases are sporadic in ALS and 5-10% of cases are familiar. More than 50 genes are known to be associated with ALS and one of them is ERBB4. In this paper, we report the case of a 53-year-old ALS patient with progressive muscle weakness and fasciculation. The patient has early onset compared to typical ALS patients and he had no cognitive decline. We performed the next generation sequencing (NGS) and in silico analysis, it predicted a highly pathogenic variant, c.2116A>G, p.Asn706Asp (N706D) in the ERBB4 gene. The amino acid residue is highly conserved among species. ERBB4 is a member of the ERBB family of receptor tyrosine kinases. ERBB4 has multiple tyrosine phosphorylation sites, including an autophosphorylation site at tyrosine 1284 residue. Autophosphorylation of ERBB4 promotes biological activity and it associated with NRG1-ERBB4 pathway. It is already known that tyrosine 128 phosphorylation of ERBB4 is decreased in patients who have ALS-associated ERBB4 mutations. We generated ERBB4 N706D construct using site-directed mutagenesis and checked the phosphorylation level of ERBB4 N706D in NSC-34 cell. We found that the phosphorylation of ERBB4 N706D was decreased compared to ERBB4 wild type, indicating a loss of function mutation in ERBB4. We also found that knockdown of ERBB4 using siRNA induces toxicity in primary neuron. We report a novel variant in ERBB4 gene leading to ALS through dysfunction of ERBB4.