Genetics of Stickler Syndrome

Stickler综合征的遗传学

• 批准号: 8335951
• 负责人: Nazli Mcdonnell
• 金额: $ 11.61万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335951
• 关键词: Affect; Amino Acids; Appearance; Arthritis; Birth; Blindness; Brain Stem; Candidate Disease Gene; Characteristics; Child; Cleft Palate; Collagen; Collagen Gene; Connective Tissue Diseases; Data; Defect; Degenerative polyarthritis; Disease; Dwarfism; Enrollment; Face; Failure; Family; Gene Mutation; Genes; Genetic; Genotype; Glycine; Goals; Growth; Head; Hearing; Hereditary Disease; Inherited; Institutional Review Boards; Laboratories; Lead; Molecular Analysis; Molecular Conformation; Mutation; Mutation Analysis; Nonsense Codon; North America; Nose; Pathology; Patients; Persons; Phenotype; Plant Roots; Procollagen; Production; RNA Splicing; Retinal; Severities; Site; Specimen; Stickler syndrome; Tissues; deafness; gel electrophoresis; genetic linkage analysis; genetic pedigree; hearing impairment; imprint; novel; premature; proband; skeletal; versican

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.

据估计，斯蒂克勒综合征（遗传性关节眼病）是北美最常见的常染色体显性结缔组织病。大约每 10,000 名新生儿中就有 1 人发生这种情况。 其典型特征是独特的面部特征、视网膜病变和听力缺陷。 50-70% 受影响的家庭涉及前胶原蛋白基因 Col2A1、Col11A1 和 Col11A2 的突变。我们通过构象敏感凝胶电泳 (CSGE) 和含异源双链片段的直接测序，完成了 48 名 Stickler 综合征先证者 Col2A1 和 Col11A1 突变的遗传学研究。这些患者是通过 IRB 批准的项目 2003-086 入组的。检测到 Col2A1 中的 24 个突变和 Col11A1 中的 4 个突变。大多数突变涉及提前终止密码子或剪接位点改变，表明单倍体不足是疾病的主要机制。只有一个案例涉及用体积更大的氨基酸取代胶原螺旋中的甘氨酸，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，其余突变位于螺旋结构域。对 28 名已识别突变的先证者进行的详细基因型/表型分析显示，所有受影响的人都具有颧骨发育不全、宽鼻梁或扁平面部轮廓等面部特征。腭裂的出现表明斯蒂克勒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变化。听力损失、股骨头衰竭、骨骼表现和过早骨关节炎虽然各不相同，但都很常见。发现的新表型发现包括三名患有 COL11A1 突变的幼儿生长迟缓，以及两名儿童的主动脉根部增大——一名患有 COL2A1 突变，另一名患有 COL11A1 突变。在 COL11A1 突变患者中发现了齿状突的额叶隆起和基底内陷进入脑干。 迄今为止，21 名先证者尚未发现致病突变。候选基因（Versacan）的分析已完成，未发现突变。 Hejtmancik 博士的实验室正在研究另一个候选基因 KCNJ13。将通过连锁分析来研究已知基因中没有突变的大家族，以发现新的致病基因。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。谱系分析和分子水平研究正在进行中以证实这一假设。