SEDT GENE--NEW INSIGHT INTO CARTILAGE BIOLOGY

SEDT 基因——软骨生物学的新见解

• 批准号: 2834715
• 负责人: STEVEN R MUMM
• 金额: $ 23.46万
• 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 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2834715
• 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扭曲。 身材矮小和骨关节炎是受影响男性面临的主要问题。 SEDT已被映射到Xp22，但SEDT基因缺陷未知。 来自阿肯色州的一个六代大型亲属的 SEDT 临床和放射学演变特征记录了出生后骨骼发育缺陷。 受影响的半合子男性在出生时具有放射学上正常的椎骨，但不久之后就会出现明显的软骨内骨形成异常，表现为椎骨中不明显的环隆起和畸形的骨骺。椎间盘退变导致身高下降和脊柱小关节破坏，股骨头颈畸形导致髋部退行性疾病。 该家族中的专性携带者女性是 SEDT 基因缺陷的杂合子，表现出微妙的异常。 累积的放射照相结果表明，主要在中轴骨骼中调节软骨内骨形成的基因受到干扰。 SEDT 基因将被识别。 具体目标是首先利用该六代亲属的连锁分析确认和缩小Xp22.2中的候选区域，然后分离和表征候选基因，并确定哪个基因负责SEDT。将使用定位克隆方法、改进的候选基因方法和基因组序列驱动方法来分离候选基因。 SEDT 基因将通过受影响个体的突变分析来识别和确认。 SEDT 基因的表征将确定这种骨骼疾病的病因，揭示软骨内骨形成的新的重要因素，并提供有关软骨生物学的重要见解。