. 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) (1). 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 (2). Mutations in ERBB4, including SNPs (3) and structural variants (4), 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 (5). 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 (6). SZ and FTD exhibit some degree of phenotypic similarity, which can cause diagnostic confusion, particularly in early stages of FTD (7). 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 (8). 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 (9). The results reported by Takahashi et al. therefore might represent an interesting first step toward identifying common genetic factors for these devastating disorders.

    References:

    . Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008 Jun;9(6):437-52. PubMed.

    . Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature. 2010 Apr 29;464(7293):1376-80. Epub 2010 Apr 14 PubMed.

    . 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.

    . Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron. 2013 Sep 18;79(6):1152-68. PubMed.

    . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20;72(2):245-56. PubMed.

    . The relationship between schizophrenia and frontotemporal dementia. J Geriatr Psychiatry Neurol. 2013 Sep;26(3):131-7. PubMed.

    . Inheritance of frontotemporal dementia. Arch Neurol. 1999 Jul;56(7):817-22. PubMed.

    . C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. Neurobiol Aging. 2013 Apr;34(4):1309.e9-10. PubMed.

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