Genetics of Stickler Syndrome

Stickler综合征(遗传性关节眼病)是北美最常见的常染色体显性遗传性结缔组织病。大约每10,000名新生儿中就有1名发生这种情况。它的典型特征是独特的面部特征、视网膜病理和听力缺陷。前胶原基因COL2A1、COL11A1和COL11A2的突变在50%-70%的受影响家庭中被发现。我们用构象敏感凝胶电泳法(CSGE)和含有异源双链片段的直接测序技术，对48例Stickler综合征先证者进行了COL2A1和COL11A1基因突变的遗传学研究。这些患者是通过IRB批准的项目2003-086入选的。检测到24个COL2A1突变和4个COL11A1突变。大多数突变涉及过早终止密码子或剪接位点的改变，这表明单倍体不足是疾病的主要机制。只有一例涉及到胶原螺旋中的甘氨酸被更大的氨基酸取代，这在导致侏儒症的II型胶原病中常见。N和C前肽各有两个突变，其余突变位于螺旋区。对28个已确认突变的先证者进行了详细的基因/表型分析，发现所有患者都有颧骨发育不良、鼻梁宽大或面部轮廓平坦等面部特征。腭裂的出现表明，Stickler综合征存在家庭内和家庭内的变异性。所有患者都有眼部表现，包括玻璃体或视网膜改变。听力损失、股骨头衰竭、骨骼表现和早产性骨关节炎是不同但常见的发现。新的表型发现包括三名患有COL11A1突变的幼儿的生长缺陷，以及两名儿童的主动脉根部增大-一名COL2A1突变，另一名COL11A1突变。在COL11A1突变的患者中，发现齿状突的额部隆起和基底凹陷进入脑干。 到目前为止，在21名先证者中还没有发现致病突变。对候选基因(范西嘉)的分析已经完成，没有发现突变。另一种候选基因KCNJ13正在海特曼奇克博士的实验室进行研究。没有已知基因突变的大型家庭将通过连锁分析来发现新的致病基因。最近的数据表明，COL2A1的印记可能是Stickler表型的家族内变异的原因。系谱分析和分子水平的研究正在进行中，以证实这一假设。

Stickler Syndrome (hereditary artho-opthalmopathy) is estimated to be the most common autosomal dominant connective tissue disease in North America. It occurs in approximately 1 in 10,000 births. It is typified by unique facial features, retinal pathology, and hearing defects. Mutations in the procollagen genes Col2A1, Col11A1 and Col11A2 have been implicated in 50-70% of affected families. We have completed genetic studies on 48 probands with Stickler syndrome for mutations in Col2A1 and Col11A1 with Conformation Sensitive Gel Electrophoresis (CSGE) and direct sequencing of heteroduplex containing fragments. The patients were enrolled through IRB-approved project 2003-086. Twenty four mutations in Col2A1 and 4 mutations in Col11A1 were detected. The majority of the mutations involve a premature termination codon or an altered splice site suggesting that haploinsufficiency is the predominant mechanism of disease. Only one case involved substitutions of a glycine in the collagen helix with a bulkier amino acid, which is frequently seen in type II collagenopathies that leads to dwarfism. There were two mutations each in the N and C propeptides, and the remaining mutations were in the helical domain. Detailed genotype/phenotype analysis of 28 probands with identified mutations revealed that facial characteristics such as malar hypoplasia, broad nasal bridge or flat facial profile were seen in all affected persons. The appearance of cleft palate showed that inter and intra-familial variability exists in Sticklers Syndrome. All patients have ocular manifestations, comprised of vitreous or retinal changes. Hearing loss, femoral head failure, skeletal manifestations and premature osteoarthritis were variable but common findings. New phenotypic findings identified included growth deficiency in three young children with COL11A1 mutations, and aortic root enlargement in two children- one with a mutation in COL2A1 and the other in COL11A1. Frontal bossing and basilar invagination of the odontoid into the brainstem was identified in patients with COL11A1 mutations. No causative mutation has been indentified to date in 21 probands. Analysis of a candidate gene (Versican) has been completed with no mutations found. Another candidate gene, KCNJ13, is being studied in Dr. Hejtmancik's laboratory. Large families without mutations in known genes will be studied by linkage analysis to discover novel causative genes. Recent data indicate that imprinting of COL2A1 may be responsible for intra-familial variability of the Stickler phenotype. Pedigree analysis and molecular level studies are under way to confirm this hypothesis.