Background: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) includes a large spectrum of neurodegenerative disorders.
Objective: To identify the relationship of ErbB4 mutation and ALS/FTD.
Methods: Here, we report an atypical case of frontal variant behavioral abnormalities at the initial stage, a stable plateau stage of 5 years, and paralysis involving both upper and lower motor neurons followed by progressive cognitive dysfunction at the advanced stage. The clinical findings suggested a diagnosis of ALS/FTD, and genetic testing revealed erb-b2 receptor tyrosine kinase 4 (ErbB4) heterozygous mutation (c.2136 T>G, p.I712M), identified in an ALS pedigree previously. We modeled mutant ErbB4 protein through the SWISS-MODEL Server, and speculated on the structural change caused by the mutation. We also identified that ErbB4 (I712M) mutation led to reduced auto-phosphorylation of ErbB4 upon neuregulin-1 (NRG1) stimulation.
Results: A functional analysis of ErbB4 mutation demonstrated an obviously decreased auto-phosphorylation of ErbB4 involving in the pathogenesis of ALS/FTD.
Conclusion: We firstly found ErbB4 mutation to be identified in ALS/FTD.
Keywords: Amyotrophic lateral sclerosis; ErbB4; I712M; frontotemporal dementia; neuregulin-1.