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145例马凡氏综合征及相关疾病（MASS）患者， 表型、二尖瓣脱垂综合征、家族性主动脉夹层） 在NHGRI遗传学诊所被发现。收集的临床数据 包括骨骼、眼部和心血管方面的详细信息 每个病人的症状。最终，我们的计划是 在BFN-1（FBN 1）中具有特定突变的临床观察 基因此外，将分析临床数据以评估有效性 马凡氏综合征的新诊断标准长期 计划对不符合诊断标准的患者进行临床随访 标准，以确定这些患者的自然史， 为他们提供最佳的管理方案。共30个新家庭（8 散发病例，22例多代）， 招募并启动分子研究。新的重组事件 进一步细化了遗传区间。物理绘图研究已经 启动，整个时间间隔定义在一系列 重叠的YAC克隆。在一部分家庭中，开角型青光眼是 连接到。青光眼是否代表了以前未被认识到的 综合征的一个方面或由连锁基因中的突变引起， 在研究中青光眼与9号染色体的联系还没有被证实。 此前报道。为了澄清 Stickler综合征表型和潜在的基因突变，我们有 启动了对26个斯蒂克勒综合征家族的临床研究， 分子手段最近有人提出， Stickler综合征可以根据眼部严重程度来定义。 调查结果。在我们研究的七个家庭中，Stickler表型是 与COL 2A 1无关。我们的数据表明，并非所有家庭 “经典”Stickler综合征在COL 2A 1基因中存在突变。我们 建议直到有足够多的家庭具有已确定的分子缺陷 Stickler综合征的亚型可根据临床表型 而不是由携带突变的基因座定义。