Kim Hyung-Goo, Kishikawa Shotaro, Higgins Anne W, Seong Ihn-Sik, Donovan Diana J, Shen Yiping, Lally Eric, Weiss Lauren A, Najm Juliane, Kutsche Kerstin, Descartes Maria, Holt Lynn, Braddock Stephen, Troxell Robin, Kaplan Lee, Volkmar Fred, Klin Ami, Tsatsanis Katherine, Harris David J, Noens Ilse, Pauls David L, Daly Mark J, MacDonald Marcy E, Morton Cynthia C, Quade Bradley J, Gusella James F
Molecular Neurogenetics Unit, Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Am J Hum Genet. 2008 Jan;82(1):199-207. doi: 10.1016/j.ajhg.2007.09.011.
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 approximately 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.
自闭症是一种病因复杂的神经发育障碍，其中遗传因素起主要作用。我们在两名独立受试者中发现了神经连接蛋白1（NRXN1）基因与自闭症谱系障碍（ASD）有关，这两名受试者患有涉及2p16.3的平衡染色体异常。在第一个病例中，核型为46,XX,ins(16;2)(q22.1;p16.1p16.3)pat，NRXN1在第5内含子内直接被破坏。重要的是，父亲在没有ASD的情况下拥有相同的染色体异常，这表明α-NRXN1的中断并非完全显性，并且必须与其他因素相互作用才能产生ASD。第二个受试者的断点为46,XY,t(1;2)(q31.3;p16.3)dn，位于NRXN1上游约750 kb处的一个2.6 Mb基因组片段内，该片段目前没有注释基因。相对于非ASD对照，对一组ASD受试者的NRXN1编码序列进行扫描发现，神经连接蛋白1中的氨基酸改变在ASD中并不高频出现。然而，编码区的一些罕见序列变异，包括分别在α-神经连接蛋白1前导序列和表皮生长因子（EGF）样结构域的保守残基中的两个错义变化，表明即使是NRXN1中的细微变化也可能导致ASD易感性。
