SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles

被引：75

作者：

Castermans, Dries ^{[1
]}

Volders, Karolien ^{[1
]}

Crepel, An ^{[2
]}

Backx, Liesbeth ^{[2
]}

De Vos, Rita ^{[3
]}

Freson, Kathleen ^{[4
]}

Meulemans, Sandra ^{[1
]}

Vermeesch, Joris R. ^{[2
]}

Schrander-Stumpel, Connie T. R. M. ^{[8
]}

De Rijk, Peter ^{[9
,10
]}

Del-Favero, Jurgen ^{[9
,10
]}

Van Geet, Chris ^{[4
,6
]}

Van De Ven, Wim J. M. ^{[5
]}

Steyaert, Jean G. ^{[2
,7
,9
]}

Devriendt, Koen ^{[2
]}

Creemers, John W. M. ^{[1
]}

机构：

[1] Catholic Univ Louvain, Dept Human Genet, Biochem Neuroendocrinol Lab, B-3000 Louvain, Belgium

[2] Catholic Univ Louvain, Ctr Human Genet, Div Clin Genet, B-3000 Louvain, Belgium

[3] Catholic Univ Louvain, Dept Med Diagnost Sci, Morphol & Mol Pathol Sect, B-3000 Louvain, Belgium

[4] Catholic Univ Louvain, Dept Mol & Cellular Med, Ctr Mol & Vasc Biol, B-3000 Louvain, Belgium

[5] Catholic Univ Louvain, Dept Human Genet, Mol Oncol Lab, B-3000 Louvain, Belgium

[6] Catholic Univ Louvain, Dept Pediat, B-3000 Louvain, Belgium

[7] Catholic Univ Louvain, Dept Child Psychiat, B-3000 Louvain, Belgium

[8] Univ Maastricht, Clin Genet Ctr, NL-6201 BL Maastricht, Netherlands

[9] VIB, Dept Mol Genet, Appl Mol Genom Grp, Louvain, Belgium

[10] Univ Antwerp, B-2610 Antwerp, Belgium

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 07期

关键词：

15Q24 MICRODELETION SYNDROME; MENTAL-RETARDATION; SPECTRUM DISORDER; NEUROBEACHIN GENE; NEUROLIGIN GENES; MEMBRANE-FUSION; MUTATIONS; EXOCYTOSIS; IDENTIFICATION; ASSOCIATION;

D O I：

10.1093/hmg/ddq013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1368 / 1378

页数：11