Disruption of neurexin 1 associated with autism spectrum disorder

被引：430

作者：

Kim, Hyung-Goo ^{[1
,2
]}

Kishikawa, Shotaro ^{[1
,2
]}

Higgins, Anne W. ^{[3
]}

Seong, Ihn-Sik ^{[1
,2
]}

Donovan, Diana J. ^{[3
]}

Shen, Yiping ^{[1
,2
]}

Lally, Eric ^{[3
]}

Weiss, Lauren A. ^{[4
,5
,6
,7
]}

Najm, Juliane ^{[8
]}

Kutsche, Kerstin ^{[8
]}

Descartes, Maria ^{[9
]}

Holt, Lynn ^{[9
]}

Braddock, Stephen ^{[10
]}

Troxell, Robin ^{[11
]}

Kaplan, Lee ^{[1
,2
]}

Volkmar, Fred ^{[12
]}

Klin, Ami ^{[12
]}

Tsatsanis, Katherine ^{[12
]}

Harris, David J. ^{[13
]}

Noens, Ilse ^{[14
]}

Pauls, David L. ^{[4
,5
,15
]}

Daly, Mark J. ^{[6
,7
,15
,16
,17
]}

MacDonald, Marcy E. ^{[1
,2
,6
,7
]}

Morton, Cynthia C. ^{[3
,6
,7
,18
]}

Quade, Bradley J. ^{[3
]}

Gusella, James E. ^{[1
,2
,6
,7
,15
,19
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Mol Neurogenet Unit, Boston, MA 02114 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[4] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Psychiat & Neurodev Genet Uni, Boston, MA 02114 USA

[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA

[6] Broad Inst Harvard, Cambridge, MA 02142 USA

[7] MIT, Cambridge, MA 02142 USA

[8] Univ Klinikum Hamburg Eppendorf, Inst Humangenet, Hamburg, Germany

[9] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA

[10] Univ Virginia Hlth Syst, Dept Pediat, Div Med Genet, Charlottesville, VA 22908 USA

[11] Univ Missouri, Dept Child Hlth, Div Med Genet, Columbia, MO 65212 USA

[12] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06520 USA

[13] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Genet, Boston, MA 02115 USA

[14] Leiden Univ, NL-2300 RA Leiden, Netherlands

[15] Autism Consortium, Boston, MA 02115 USA

[16] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[17] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[18] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA

[19] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2008年 / 82卷 / 01期

关键词：

D O I：

10.1016/j.ajhg.2007.09.011

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs similar to 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.

引用

页码：199 / 207

页数：9

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