HEREDITY DISORDERS OF CONNECTIVE TISSUE--CLINICAL AND MOLECULAR STUDIES

结缔组织遗传性疾病——临床和分子研究

• 批准号: 6162571
• 负责人: C A FRANCOMANO
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 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/6162571
• 关键词: Marfan syndrome; achondroplasia; child (0-11); clinical research; collagen disorder; congenital skeletal disorder; connective tissue disorder; fibrillin; gene mutation; genetic disorder; genetics; human genetic material tag; human subject; human tissue; linkage mapping; molecular cloning; molecular genetics; molecular pathology

A total of 145 patients with Marfan syndrome and related conditions (MASS phenotype, mitral valve prolapse syndrome, familial aortic dissection) have been seen in the NHGRI Genetics Clinic. Clinical data collected included detailed information on skeletal, ocular and cardiovascular manifestations in each patient. Eventually, the plan is to correlate clinical observations with specific mutations in the fibrillin-1 (FBN1) gene. Additionally, clinical data will be analyzed to assess the validity of proposed new diagnostic criteria for Marfan syndrome. Long-term clinical follow-up is planned for patients not fulfilling the diagnostic criteria, to determine the natural history of these patients and also the optimal management scheme for them. A total of 30 new families (8 sporadic cases, 22 multigenerational) with Nail-Patella syndrome were recruited and molecular studies initiated. Novel recombination events further refined the gentic interval. Physical mapping studies have been initiated and the entire NPS interval is defined in a series of overlapping YAC clones. In a subset of families, open angle glaucoma is linked to NPS. Whether glaucoma represents a previously unrecognized aspect of the syndrome or results from mutation(s) in a linked gene, is under investigation. Linkage of glaucoma to chromosome 9 has not been reported previously. In an effort to clarify the relationship between the Stickler syndrome phenotype and underlying gene mutations, we have initiated the study of 26 Stickler syndrome families by clinical and molecular means. Recently it has been proposed that two subtypes of Stickler syndrome can be defined based on the severity of ocular findings. In seven of the families we studied, the Stickler phenotype was not linked to COL2A1. Our data demonstrate that not all families with "classical" Stickler syndrome have mutations in the COL2A1 gene. We suggest that until sufficient families with identified molecular defects are studied, Stickler syndrome subtypes be based on clinical phenotype alone and not defined by the locus carrying the mutation.

共有145例Marfan综合征和相关疾病患者（质量 表型，二尖瓣脱垂综合征，家族主动脉夹层） 在NHGRI遗传学诊所已看到。收集的临床数据 包括有关骨骼，眼和心血管的详细信息 每个患者的表现。最终，计划是关联 纤维素-1中具有特异性突变的临床观察（FBN1） 基因。此外，将分析临床数据以评估有效性 提议的Marfan综合征的新诊断标准。长期 计划针对不履行诊断的患者进行临床随访 标准，确定这些患者的自然历史以及 他们的最佳管理计划。共有30个新家庭（8个 零星病例，有22种多代）患有指甲帕特拉综合征 招募和分子研究开始了。新的重组事件 进一步完善了绅士间隔。物理图研究已经 启动和整个NP间隔是在一系列中定义的 重叠的YAC克隆。在家庭的一部分中，开头青光眼是 链接到NP。青光眼是否代表先前未知的 综合征的方面或链接基因中突变的结果， 正在调查。青光眼与9号染色体的连接尚未 先前报道了。为了澄清 Stickler综合征表型和基础基因突变，我们有 通过临床和 分子平均值。最近有人提出了两个亚型 可以根据眼的严重程度来定义Stickler综合征 发现。在我们研究的七个家庭中，Stickler表型是 与COL2A1无关。我们的数据表明，并非所有的家庭 “经典”棒状综合征在COL2A1基因中具有突变。我们 建议直到有足够的分子缺陷的家庭 研究了Stickler综合征亚型基于临床表型 单独，不是由携带突变的基因座定义的。