SEDT GENE--NEW INSIGHT INTO CARTILAGE BIOLOGY

SEDT 基因——软骨生物学的新见解

• 批准号: 6375202
• 负责人: STEVEN R MUMM
• 金额: $ 20.86万
• 依托单位: BARNES-JEWISH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375202
• 关键词: HeLa cells; articular cartilage; artificial chromosomes; autosomal recessive trait; bone development disorder; cartilage development; clinical research; computer assisted sequence analysis; family genetics; gel electrophoresis; gene expression; gene mutation; genetic carriers; genetic markers; genetic screening; human genetic material tag; in situ hybridization; linkage mapping; molecular cloning; northern blottings; polymerase chain reaction; sex linked trait; southern blotting; tissue /cell culture

Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive osteochondrodysplasia characterized by malformation of the vertebrae and distortions of the epiphyses within major joints. Short stature and osteoarthritis are the principal problems suffered by affected men. SEDT has been mapped to Xp22, but the SEDT gene defect is unknown. Characterization of the clinical and radiographic evolution of SEDT in a large six-generation kindred from Arkansas has documented a postnatal defect of skeletal development. Affected hemizygous males have radiographically normal vertebrae at birth, but soon after manifest aberrant endochondral bone formation reflected by an inapparent ring apophysis in vertebrae and mishappen epiphyses. Degeneration of intervertebral discs leads to loss of height and destruction of spinal facet joints, and femoral head and neck deformity cause degenerative disease of the hips. Obligate carrier women in this kindred, heterozygous for the SEDT gene defect, demonstrate subtle abnormalities. The cumulative radiographic findings suggest a disturbance in a gene that conditions endochondral bone formation primarily in the axial skeleton. The SEDT gene will be identified. Specific aims first confirm and narrow the candidate region in Xp22.2 using linkage analysis for this six-generation kindred, then isolate and characterize candidate genes, and identify which gene is responsible for SEDT. Candidate genes will be isolated using a positional cloning approach, a modified candidate gene approach, and a genomic sequence driven approach. The SEDT gene will be identified and confirmed by mutational analysis of affected individuals. Characterization of the SEDT gene will establish the etiology for this skeletal disorder, reveal a new and important factor in endochondral bone formation, and provide significant insight concerning cartilage biology.

迟发性脊椎骨骺发育不良（SEDT）是一种x连锁隐性骨软骨发育不良，其特征是椎骨畸形和主要关节内骨骺变形。矮小和骨关节炎是受影响男性的主要问题。SEDT已定位于Xp22，但SEDT基因缺陷尚不清楚。表征SEDT的临床和影像学演变在一个大的六代亲属从阿肯色州已经记录了出生后的骨骼发育缺陷。受影响的半合子雄性在出生时放射学上的椎骨是正常的，但很快就会出现异常的软骨内骨形成，表现为椎骨不明显的环形突和畸形的骨骺。椎间盘退变导致高度下降和脊柱小关节破坏，股骨头和股骨颈畸形导致髋关节退行性疾病。专性携带者女性，杂合SEDT基因缺陷，表现出微妙的异常。累积的x线检查结果表明，一个基因的干扰，主要是在轴骨条件软骨内骨形成。SEDT基因将被鉴定。具体目的首先通过对该6代亲缘系的连锁分析，确定和缩小Xp22.2中的候选区域，然后分离和表征候选基因，确定哪一个基因负责SEDT。候选基因将使用位置克隆方法、修饰候选基因方法和基因组序列驱动方法进行分离。SEDT基因将通过受影响个体的突变分析来鉴定和确认。SEDT基因的鉴定将建立这种骨骼疾病的病因学，揭示软骨内骨形成的一个新的重要因素，并为软骨生物学提供重要的见解。