Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism
Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism
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DOI：
10.1159/000172086
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发表时间：
2008-01-01
影响因子：
1.7
通讯作者：
Fan, Y. -S.
中科院分区：
文献类型：
--
作者：
Xu, S.;Han, J. C.;Fan, Y. -S.
WAGR综合征是一种罕见的由11p14-p12区域缺失引起的基因组疾病。大多数WAGR患者都有智力低下和行为问题，超过20%的患者还具有自闭症的特征。虽然Wilms肿瘤/泌尿生殖系统异常和无虹膜分别是由WT1和PAX6缺失引起的，但WAGR综合征中智力低下和自闭症的基因组原因尚不清楚。使用寡核苷酸阵列，我们已经确定了31名患者的11p14-p12缺失，并确定了每个缺失涉及的所有基因。缺失的基因大小从4.9到23Mb不等，涵盖18-62个基因(平均40个)。除WT1和PAX6外，所有患者均存在PRRG4(跨膜型γ-羧基谷氨酸蛋白4)缺失。其中大部分缺失脑源性神经营养因子和SLC1A2[溶质载体家族1(胶质高亲和力谷氨酸转运体)成员2]。BDNF和SLC1A2缺失在自闭症患者中发生的频率高于非自闭症患者。对这些基因功能的文献综述表明，SLC1A2、PRRG4和BDNF的单倍体不足可能与智力低下和行为问题有关。特别是，BDNF可能调节WAGR患者的自闭症风险，因为它与作为MECP2靶点的Rett综合征的联系表明。我们观察到，在WAGR患者中，所有的从头缺失都发生在遗传自父亲的第11号染色体上，这意味着在精子发生过程中容易发生从头突变，并可能参与WAGR患者的认知障碍。版权所有(C)2008 S.Karger AG，巴塞尔
WAGR (Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome is a rare genomic disorder caused by deletion of the 11p14-p12 chromosome region. The majority of WAGR patients have mental retardation and behavioral problems, and more than 20% of the patients also have features of autism. While the Wilms tumor/genitourinary anomalies and aniridia are caused by deletion of WT1 and PAX6 respectively, the genomic cause of mental retardation and autism in WAGR syndrome remains unknown. Using oligonucleotide arrays, we have characterized the 11p14-p12 deletions in 31 patients and identified all the genes involved in each deletion. The deletions had sizes ranging from 4.9 to 23 Mb that encompass 18-62 genes (40 on average). In addition to WT1 and PAX6, all the patients had deletion of PRRG4 (transmembrane gamma-carboxyglutamic acid protein 4). The majority of them had deletion of BDNF (brain-derived neurotrophic factor) and SLC1A2 [ solute carrier family 1 (glial high affinity glutamate transporter) member 2]. Deletion of BDNF and SLC1A2 occurred in patients with autism more frequently than in those without autism. Literature review on the functions of the genes suggests that haploin-sufficiency of SLC1A2, PRRG4, and BDNF may contribute to mental retardation and behavioral problems. In particular, BDNF may modulate the risk of autism in WAGR patients as suggested by its link with Rett syndrome as a target of MECP2. We observed that all the de novo deletions occurred in the chromosome 11 inherited from the father in the families genotyped, implying a predisposition for de novo mutations occurring in spermatogenesis and possible involvement of imprinting in cognitive impairment in WAGR patients. Copyright (C) 2008 S. Karger AG, Basel