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Rare variants analysis of neurexin-1 in autism reveals a novel start codon mutation affecting protein levels at synapses

Camacho-Garcia, Rafael J.a; Hervás, Amaiac; Toma, Claudiod,e; Balmaña, Noemíc; Cormand, Brud,e,f; Martinez-Mir, Amaliaa; Scholl, Francisco G.a,b

doi: 10.1097/YPG.0000000000000013
Brief Reports

Neurexins are synaptic plasma membrane proteins encoded by three genes (NRXN1, -2, -3) with alternative promoters. Mutations in neurexin genes have been identified in different neurodevelopmental disorders, including autism. Recently, two point mutations altering the translation initiation site of NRXN1β (c.−3G>T and c.3G>T) have been described in patients with autism and mental retardation. In this study, we analyzed the NRXN1β gene in a sample of 153 patients with autism. We report the identification of a novel mutation, c.3G>A (p.Met1), affecting the translation initiation site. Expression analysis showed that the c.3G>A mutation switches the translation start site of NRXN1β to an in-frame downstream methionine and decreases synaptic levels of the mutant protein in cultured neurons. These data reinforce a role for synaptic defects of NRXN1β in neurodevelopmental disorders.

aSeville Biomedical Research Institute (IBiS), Virgen del Rocio University Hospital, CSIC

bDepartment of Medical Physiology and Biophysics, University of Seville, Seville

cChild and Adolescent Mental Health Unit, Mutua de Terrassa University Hospital, Terrassa

dDepartment of Genetics, Faculty of Biology, University of Barcelona

eBiomedical Network Research Centre on Rare Diseases (CIBERER)

fInstitute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain

Correspondence to Francisco G. Scholl, PhD, Instituto de Biomedicina de Sevilla (IBiS), Campus del Hospital Universitario Virgen del Rocio, Avda, Manuel Siurot s/n, Sevilla 41013, Spain Tel: +34 955923042; fax: +34 955923101; e-mail: fgs@us.es

Received February 4, 2013

Accepted August 7, 2013

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins