A Novel Dominant COL11A1 Mutation Resulting in a Severe Skeletal Dysplasia
A Novel Dominant COL11A1 Mutation Resulting in a Severe Skeletal Dysplasia
复制标题
DOI：
10.1002/ajmg.a.36688
复制
发表时间：
2014-10-01
影响因子：
2
通讯作者：
Hopkin, Robert J.
中科院分区：
文献类型：
--
作者：
Hufnagel, Sophia B.;Weaver, K. Nicole;Hopkin, Robert J.
XI 型胶原蛋白 α-1 链基因 (COL11A1) 的突变会导致蛋白质结构发生变化，从而改变其与 II 型和 V 型胶原蛋白的相互作用，从而导致软骨和眼玻璃体异常。最常见的 XI 型胶原病是显性遗传的 Stickler 或 Marshall 综合征，而严重的隐性骨骼发育不良（例如纤维软骨形成）的发生频率较低。我们描述了一个因新型显性遗传 COL11A1 突变引起的严重骨骼发育不良的家庭。兄弟姐妹均患有严重近视、听力丧失、小肢畸形、长骨干骺端增宽、小颌畸形和需要气管造口术的气道损害。第一个孩子活了 2 年多，第二个孩子在 5 个月大时去世。他们的母亲患有轻度四肢根状缩短、短指和严重近视。 COL11A1 的测序揭示了 COL11A1 中的一种新的有害杂合突变，涉及兄弟姐妹的三螺旋结构域，以及其母亲的嵌合突变，表明种系嵌合现象以及随后的显性遗传。这是首次报道的 COL11A1 显性遗传突变与严重骨骼发育不良相关的个体。骨骼受累类似于纤维软骨形成，但较轻，并且允许存活到围产期之后。这些病例凸显了导致显着骨骼发育不良的新型显性 COL11A1 突变和胶原病的表型异质性。 (C) 2014 年 Wiley 期刊公司。
Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in abnormalities in cartilage and ocular vitreous. The most common type XI collagenopathies are dominantly inherited Stickler or Marshall syndromes, while severe recessive skeletal dysplasias, such as fibrochondrogenesis, occur less frequently. We describe a family with a severe skeletal dysplasia caused by a novel dominantly inherited COL11A1 mutation. The siblings each presented with severe myopia, hearing loss, micromelia, metaphyseal widening of the long bones, micrognathia, and airway compromise requiring tracheostomy. The first child lived for over 2 years, while the second succumbed at 5 months of age. Their mother has mild rhizomelic shortening of the limbs, brachydactyly, and severe myopia. Sequencing of COL11A1 revealed a novel deleterious heterozygous mutation in COL11A1 involving the triple helical domain in both siblings, and a mosaic mutation in their mother, indicating germline mosaicism with subsequent dominant inheritance. These are the first reported individuals with a dominantly inherited mutation in COL11A1 associated with a severe skeletal dysplasia. The skeletal involvement is similar to, yet milder than fibrochondrogenesis and allowed for survival beyond the perinatal period. These cases highlight both a novel dominant COL11A1 mutation causing a significant skeletal dysplasia and the phenotypic heterogeneity of collagenopathies. (C) 2014 Wiley Periodicals, Inc.