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About the Authors:
Wei Tan
Affiliation: Basic Science Program, Science Application International Corporation - Frederick, National Cancer Institute at Frederick, Frederick, Maryland, United States of America
Michael Dean
Affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America
Amanda J. Law
* E-mail: [email protected]
Affiliation: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America
Introduction
Alternative splicing is a key element in gene regulation that increases proteome diversity and the coding potential of the human genome. Evidence from expressed sequence tag, cDNA, genome-wide tiling and splicing microarray datasets demonstrate that alternative splicing occurs in >90% of genes [1]–[3]. Alternative splicing is especially prevalent in the brain which may account for the high incidence of genetic brain disorders.
Linkage and association analyses have identified neuregulin 1 and its receptor ErbB4 as susceptibility genes for schizophrenia [4]–[7] and recently partial deletions of the ErbB4 gene have been reported in the disorder [8]. ErbB4 is a member of the receptor tyrosine kinase family, which also includes epidermal growth factor receptor (EGFR/HER1/ErbB1), HER2/ErbB2, and HER3/ErbB3. The human ErbB4 gene spans 1.16 Mb (megabases) on chromosome 2q34 and has been annotated to consist of 28 exons. To date, four structurally and functionally distinct splice isoforms of the human ErbB4 gene have been described. The JM-ErbB4 isoforms differ within their extracellular juxtamembrane domain annotated as based on differential inclusion of exon 15 (JM-a) or exon 16 (JM-b), which renders them susceptible or resistant, respectively, to processing by matrix metalloproteases [9], [10]. The ErbB4-CYT isoforms arise from additional splicing of the cytoplasmic tail region based on the inclusion (CYT-1) or exclusion (CYT-2) of exon 26, encoding 16 amino acids [11].
Previous studies have demonstrated that a haplotype consisting of three single nucleotide polymorphisms (SNPs; rs707284, rs839523 and rs7598440) in the human ErbB4 gene is associated with increased risk for schizophrenia, augmented expression of the ErbB4 CYT-1 phosphoinositide 3-kinase (PI3K)-linked isoform in the brain of patients and altered frontotemporal structural connectivity in normal humans measured with magnetic resonance imaging (MRI) techniques [6], [7], [12]. The mechanism by which the risk SNPs influence ErbB4 CYT-1 expression is...