Father‐to‐daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5′ untranslated region of the NIPBL Gene
Father‐to‐daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5′ untranslated region of the NIPBL Gene
复制标题
由 NIPBL 基因 5-2 非翻译区突变引起的 Cornelia de Lange 综合征的父女传播
作者：
G. Borck;Mohamed Zarhrate;C. Cluzeau;E. Bal;J. Bonnefont;A. Munnich;V. Cormier;L. Colleaux
Cornelia de Lange综合征（CdLS，又称Brachmann de Lange综合征）是一种以典型的面部畸形、生长发育和智力迟钝、小头畸形和各种畸形为特征的发育障碍。在约40%的报告病例中发现了NIPBL基因突变，这表明要么是遗传异质性，要么是目前的筛查策略未检测到一些NIPBL突变。我们筛选了21例先前未发现NIPBL异常的5 ‘非翻译区（5 ’ utr）和NIPBL基因近端启动子突变的患者。我们在一名患病女孩及其轻度患病父亲的翻译起始密码子上游1321个核苷酸外显子（c.‐321_‐320delCCinsA）中发现了杂合缺失插入突变。这种突变改变了高度保守的核苷酸，在400个对照等位基因中未发现，在父亲中重新出现，并与家族中的疾病共分离。通过实时定量PCR，我们发现与对照组相比，患者淋巴细胞中NIPBL mRNA的表达降低。最后，我们发现，当亚克隆到荧光素酶报告载体时，突变导致报告基因活性显著降低。我们的研究结果表明，NIPBL基因5 '非编码区突变可能参与CdLS的发病机制。影响该基因区域的突变可能与较温和的表型有关。植物学报，27(8),2006。©2006 Wiley‐Liss, Inc。
Cornelia de Lange syndrome (CdLS; also called Brachmann de Lange syndrome) is a developmental disorder characterized by typical facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Mutations in the NIPBL gene have been identified in ∼40% of reported cases, suggesting either genetic heterogeneity or that some NIPBL mutations are not detected by current screening strategies. We screened a cohort of 21 patients with no previously identified NIPBL anomaly for mutations in the 5′ untranslated region (5′UTR) and the proximal promoter of the NIPBL gene. We identified a heterozygous deletion‐insertion mutation in exon 1, 321 nucleotides upstream of the translation initiation codon (c.‐321_‐320delCCinsA) in one affected girl and her mildly affected father. This mutation altered highly conserved nucleotides, was not found in 400 control alleles, arose de novo in the father, and cosegregated with the disease in the family. Using real‐time quantitative PCR, we showed that NIPBL mRNA expression was lowered in patients' lymphocytes compared to control samples. Finally, we showed that, when subcloned into a luciferase reporter vector, the mutation leads to a significant reduction of reporter gene activity. Our results demonstrate that mutations in the 5′ noncoding region of the NIPBL gene can be involved in the pathogenesis of CdLS. Mutations affecting this region of the gene might be associated with a milder phenotype. Hum Mutat 27(8), 731–735, 2006. © 2006 Wiley‐Liss, Inc.