Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.
EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.
Genet Med. 2017 Sep;19(9):1013-1021. doi: 10.1038/gim.2017.11. Epub 2017 Mar 16.
Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown.
We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families.
We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation.
Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.
Blepharocheilodontic (BCD) 综合征是一种罕见的常染色体显性遗传病，其特征为眼睑畸形、唇裂/腭裂和外胚层发育不良。BCD 综合征的分子基础尚不清楚。
我们从 8 个家系中招募了 11 名患者，对 5 个家系中的新生 BCD 综合征病例进行外显子组测序，并对其余 3 个家系进行靶向 Sanger 测序。
我们发现了 5 个 CDH1 杂合错义突变和 3 个 CTNND1 杂合截断突变，导致功能丧失或杂合性不足。由于队列规模较小，无法建立详细的基因型-表型相关性；然而，在 CDH1 突变的情况下，表型似乎更为严重。CDH1 突变的功能分析证实了其有害影响，并提示 E-钙黏蛋白降解加速。
CDH1 编码 E-钙黏蛋白的突变以前在遗传性弥漫性胃癌以及非综合征性唇裂/腭裂中被报道过。CTNND1 的突变以前从未被报道过。编码蛋白 p120ctn 可防止 E-钙黏蛋白内吞，并稳定其在细胞表面的定位。在各种动物模型中条件性敲除 Cdh1 和 Ctnnd1 可诱导出与 BCD 综合征相似的特征，突出了 E-钙黏蛋白-p120ctn 相互作用在眼睑、颅面和牙齿发育中的关键作用。我们的数据证明 BCD 综合征是由于 CDH1 和 CTNND1 突变导致的 CDH1 通路相关疾病，并拓宽了 E-钙黏蛋白异常的表型谱。遗传医学在线发表 2017 年 3 月 9 日。
