. ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19. Am J Hum Genet. 2013 Oct 8; PubMed.


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  1. This new discovery is exciting. In addition to the welcome identification of another critical player in the pathogenesis of ALS, ErbB receptor tyrosine kinases and neuregulins are much-studied groups of molecules, so there should be a lot of resources (mice, cell lines, receptor agonists, and antagonists) already available to launch the basic and translational studies needed to follow up the gene identification. Further, the apparent lack of dementia is important considering the current focus on the emergence of FTD in a large segment of both familial and sporadic ALS. Is the loss of non-motor frontal neurons just very subtle in these patients, or in fact are there two quite distinct pathways for ALS—one involving additional prefrontal loss, and one not?

  2. A new study by Takahashi et al. in the American Journal of Human Genetics identifies a role for loss-of-function mutations in the gene ERBB4 in familial amyotrophic lateral sclerosis (FALS). The mutation was discovered by whole-genome sequencing (WGS) in a Japanese family and confirmed in a Canadian patient. ErbB4 is a receptor tyrosine kinase that is activated by the neuregulin family of signaling factors, notably neuregulin-1 (NRG1) (Mei and Xiong, 2008). In the brain, NRG1- ErbB4 signaling is crucial to the development and maintenance of inhibitory circuitry, particularly by regulating the migration and synaptic plasticity of fast-spiking interneurons, in which ErbB4 is specifically expressed (Fazzari et al., 2010). Mutations in ERBB4, including SNPs (Hatzimanolis et al., 2013) and structural variants (Walsh et al., 2008), have been linked to schizophrenia (SZ) in multiple populations. Recent studies in mouse models show that cell type-specific ablation of ErbB4 in cortical interneurons results in SZ-like behavioral phenotypes (Del Pino et al., 2013). It is therefore intriguing that disrupted NRG1-ErbB4 signaling in a different location and cellular population (i.e., spinal motor neurons) underlies FALS—could this finding indicate that the cellular pathophysiologies of SZ and FALS are more closely related than previously thought?

    Frontotemporal dementia (FTD) may represent an important domain that could possibly link SZ to FALS. In recent years, ALS and FTD have been associated with mutations in several genes, such as C90RF72 (Dejesus-Hernandez et al., 2011). SZ and FTD exhibit some degree of phenotypic similarity, which can cause diagnostic confusion, particularly in early stages of FTD (Cooper and Ovsiew, 2013). More than one report has indicated that family members of patients with SZ or schizoaffective disorder are more likely to suffer from FTD, indicating that susceptibility for both diseases may be heritable (Chow et al., 1999). These observations have led investigators to suspect a common genetic basis for SZ and FALS; however, a recent study did not find C9ORF72 mutations in an SZ population (Huey et al., 2013). The results reported by Takahashi et al. therefore might represent an interesting first step toward identifying common genetic factors for these devastating disorders.


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    . Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients. Transl Psychiatry. 2013;3:e264. PubMed.

    . Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008 Apr 25;320(5875):539-43. PubMed.

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