Genetics of Stickler Syndrome

Stickler综合征（遗传性关节眼病）估计是北美最常见的常染色体显性结缔组织病。它发生在大约1/10，000出生。 它的典型特征是独特的面部特征，视网膜病变和听力缺陷。 前胶原基因Col 2A 1、Col 11 A1和Col 11 A2的突变涉及50-70%的受影响家族。我们用构象敏感凝胶电泳（CSGE）和直接测序法对48例Stickler综合征先证者进行了Col 2A 1和Col 11 A1突变的遗传学研究。患者通过IRB批准的项目2003-086入组。共检测到24个Col 2A 1突变和4个Col 11 A1突变。大多数突变涉及提前终止密码子或改变的剪接位点，表明单倍不足是疾病的主要机制。只有一例涉及胶原螺旋中的甘氨酸被体积较大的氨基酸取代，这在导致侏儒症的II型胶原病中常见。在N和C前肽中各有两个突变，其余突变在螺旋结构域中。详细的基因型/表型分析的28个先证者与确定的突变显示，面部特征，如颧骨发育不全，宽鼻梁或扁平的面部轮廓被认为是在所有受影响的人。腭裂的出现表明Sticklers综合征存在家族间和家族内的变异性。所有患者都有眼部表现，包括玻璃体或视网膜的变化。听力损失、股骨头衰竭、骨骼表现和早期骨关节炎是可变但常见的结果。发现的新表型结果包括三名患有COL 11 A1突变的幼儿的生长缺陷，以及两名儿童的主动脉根扩大-一名患有COL 2A 1突变，另一名患有COL 11 A1突变。在COL 11 A1突变的患者中发现了齿状突额部隆起和基底部内陷入脑干。 迄今为止，在21名先证者中未发现致病突变。一个候选基因（Versican）的分析已经完成，没有发现突变。另一个候选基因KCNJ 13正在Hejtmancik博士的实验室进行研究。在已知基因中没有突变的大家族将通过连锁分析来研究，以发现新的致病基因。最近的数据表明，COL 2A 1的印迹可能是负责Stickler表型的家族内变异。正在进行谱系分析和分子水平的研究，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.