title: Screening of human LPHN3 for variants with a potential impact on ADHD susceptibility.
abstract: Attention deficit hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood, and often has effects detectable into adulthood. Advances in genetic linkage and association analysis have begun to elucidate some of the genetic factors underlying this complex disorder. Recently, we identified LPHN3, a novel ADHD susceptibility gene harbored in 4q, and showed that a LPHN3 common haplotype confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Here we present the mutational analysis of the entire coding region of LPHN3 in a cohort of 139 ADHD subjects and 52 controls from across the USA. We identified 21 variants, of which 14 have been reported and 7 are novel. These include 5 missense, 8 synonymous, and 8 intronic changes. Interestingly, neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations, suggesting that non-coding variations determining the quantity and/or quality of LPHN3 isoforms are the likely contributors to this common behavioral disorder.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-3717, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Domené
authors.forename: Horia
authors.initials: H
authors.lastname: Stanescu
authors.forename: Deeann
authors.initials: D
authors.lastname: Wallis
authors.forename: Bradford
authors.initials: B
authors.lastname: Tinloy
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Pineda
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000595:Amino Acid Sequence; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics*; D018000:Receptors, Peptide / Q000737:chemistry / Q000235:genetics*; D015203:Reproducibility of Results; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C513284:ADGRL3 protein, human; D020033:Protein Isoforms; D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide