Rasool Mahmood, Schuster Jens, Aslam Muhammad, Tariq Muhammad, Ahmad Ilyas, Ali Amjad, Entesarian Miriam, Dahl Niklas, Baig Shahid Mahmood
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, 751 85, Uppsala, Sweden.
J Hum Genet. 2008;53(10):894-898. doi: 10.1007/s10038-008-0323-x. Epub 2008 Aug 9.
Isolated hypodontia, or congenital absence of one to six permanent teeth (OMIM 300606), is a common condition that affects about 20% of individuals worldwide. We identified two extended Pakistani pedigrees segregating X-linked hypodontia with variable expressivity. Affected males show no other associated anomalies, and obligate carrier females have normal dentition. We analyzed the families with polymorphic markers in the ectodysplasin A (EDA) gene region and obtained significant linkage to the phenotype in each pedigree (Z(max) 3.29 and 2.65, respectively, at theta = 0.00). Sequence analysis of the coding regions of EDA revealed a novel missense mutation c.1091T>C resulting in a methionine to threonine substitution (p.M364T) in the tumor necrosis factor (TNF) homology domain. Met364 is a highly conserved residue located on the outer surface of the EDA protein. From our findings, we suggest that the mutation disturbs but does not destroy the EDA structure, resulting in the partial and unusually mild ED phenotype restricted to hypodontia.
孤立性恒牙先天缺失，即先天性缺失一至六颗恒牙（OMIM 300606），是一种常见病症，全球约20%的人受其影响。我们鉴定出两个巴基斯坦大家族，其中X连锁恒牙先天缺失呈可变表达。患病男性无其他相关异常，而必然携带者女性牙齿排列正常。我们用外胚层发育不良蛋白A（EDA）基因区域的多态性标记对这些家族进行分析，在每个家系中均发现该标记与表型有显著连锁关系（在θ = 0.00时，Z(max)分别为3.29和2.65）。对EDA编码区的序列分析发现一个新的错义突变c.1091T>C，导致肿瘤坏死因子（TNF）同源结构域中的甲硫氨酸替换为苏氨酸（p.M364T）。Met364是位于EDA蛋白外表面的一个高度保守的残基。根据我们的研究结果，我们认为该突变扰乱但未破坏EDA结构，导致了局限于恒牙先天缺失的部分且异常轻微的外胚层发育不良表型。
