title: SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles.
abstract: Autism is a neurodevelopmental disorder characterized by impaired social reciprocity, impaired communication and stereotypical behaviors. Despite strong evidence for a genetic basis, few susceptibility genes have been identified. Here, we describe the positional cloning of SCAMP5, CLIC4 and PPCDC as candidate genes for autism, starting from a person with idiopathic, sporadic autism carrying a de novo chromosomal translocation. One of these genes, SCAMP5 is silenced on the derivative chromosome, and encodes a brain-enriched protein involved in membrane trafficking, similar to the previously identified candidate genes NBEA and AMISYN. Gene silencing of Nbea, Amisyn and Scamp5 in mouse beta-TC3 cells resulted in a 2-fold increase in stimulated secretion of large dense-core vesicles (LDCVs), while overexpression suppressed secretion. Moreover, ultrastructural analysis of blood platelets from the patients with haploinsufficieny of one of the three candidate genes, showed morphological abnormalities of dense-core granules, which closely resemble LDCVs. Taken together, this study shows that in three independent patients with autism three different negative regulators of LDCV secretion are affected, respectively, suggesting that in at least a subgroup of patients the regulation of neuronal vesicle trafficking may be involved in the pathogenesis of autism.
authors.affiliation: Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Dries
authors.initials: D
authors.lastname: Castermans
authors.forename: Karolien
authors.initials: K
authors.lastname: Volders
authors.forename: An
authors.initials: A
authors.lastname: Crepel
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Backx
authors.forename: Rita
authors.initials: R
authors.lastname: De Vos
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
authors.forename: Sandra
authors.initials: S
authors.lastname: Meulemans
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
authors.forename: Connie T R M
authors.initials: CT
authors.lastname: Schrander-Stumpel
authors.forename: Peter
authors.initials: P
authors.lastname: De Rijk
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Chris
authors.initials: C
authors.lastname: Van Geet
authors.forename: Wim J M
authors.initials: WJ
authors.lastname: Van De Ven
authors.forename: Jean G
authors.initials: JG
authors.lastname: Steyaert
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
mesh_terms: D000328:Adult; D000818:Animals; D001321:Autistic Disorder / Q000097:blood / Q000235:genetics*; D001792:Blood Platelets / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002884:Chromosomes, Human, Pair 15; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D022142:Secretory Vesicles / Q000378:metabolism*; D014178:Translocation, Genetic
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C498595:NBEA protein, human; D009419:Nerve Tissue Proteins; C540013:SCAMP5 protein, human; C465215:STXBP6 protein, human