Common genetic variation in Neuregulin 3 ( NRG3 ) influences risk for schizophrenia and impacts NRG3 expression in human brain

Abstract

Structural and polymorphic variations in Neuregulin 3 (NRG3), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genomewide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5′ exon (P = 1.097E −12 to 1.445E −15 ). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association.clinical genetics | development | ErbB4 | neuregulin | NRG1

Neuregulin 3 Knockout Mice Exhibit Behaviors Consistent with Psychotic Disorders

“…A follow-up association study across the linkage peak identified a strong association of several intronic single nucleotide polymorphisms (SNPs) in NRG3 with the ‘Delusion' factor as a measure of various delusions exhibited by patients [9,10]. Similar results linking NRG3 and various types of delusions were obtained in other populations [7,11], suggesting that genetic variants of NRG3 could contribute to the risk of schizophrenia.…”

“…NRG3 is an ErbB4 ligand associated with the increased risk for neuropsychiatric disorders, including schizophrenia [5,6,7,10]. However, the role of NRG3 in the neurobiological mechanisms of abnormal behaviors consistent with major psychiatric disorders remains poorly understood.…”

“…Many genetic loci associated with schizophrenia only impart a small genetic risk [4]. Genetic studies in schizophrenia demonstrate that risk variants in Neuregulin 3 (NRG3) are associated with cognitive and psychotic symptom severity, accompanied by increased expression of prefrontal cortical NRG3 [5,6,7]. Our studies found a linkage signal in chromosome 10q22, containing NRG3, in an Ashkenazi Jewish population, and a Han Chinese population that showed association with schizophrenia [8,2].…”

Diagnostic yield of array comparative genomic hybridization in adults with autism spectrum disorders

“…NRG3-ERBB4 binding activates intracellular signaling cascades and the induction of cellular responses, including neuroblast proliferation, migration and differentiation. 20,21 Recent studies have implicated this gene as a susceptibility locus for neuropsychiatric disorders, including schizophrenia and autism. 22,23 Although NRG3 is a compelling candidate gene for autism in the literature, because whether this intronic deletion would affect splicing or expression of NRG3 is unknown, this deletion was considered a VUS.…”

Busca de genes associados à resposta ao teste de Montenegro para antígenos de Leishmania.

“…que codifica receptores transmenbrana da tirosina (ErbB3 e ErbB4) que são membros de fatores de crescimento da epiderme (KAO, et al 2010), podendo dessa forma ter alguma participação na infecção da leishmaniose cutânea.…”