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，其特征是脊椎畸形和主要关节内骨骺变形。 身材矮小和骨关节炎是受影响男性的主要问题。 SEDT已被定位到Xp22，但SEDT基因缺陷是未知的。 在阿肯色州的一个大型六代亲属中，SEDT的临床和影像学演变特征记录了骨骼发育的出生后缺陷。 受影响的半合子男性在出生时X线检查正常的椎骨，但不久后表现出异常的软骨内骨形成，反映在椎骨和畸形骨骺中的不明显的环形隆起。椎间盘退变导致高度丢失和脊柱小关节破坏，股骨头和颈畸形导致髋关节退行性疾病。 在这个家族中，SEDT基因缺陷杂合子的专性携带者女性表现出细微的异常。 累积的影像学结果表明，在一个基因的干扰，条件软骨内骨形成主要是在轴骨。将鉴定SEDT基因。 具体的目的是首先确认和缩小的候选区域在Xp22.2使用连锁分析这六代亲属，然后分离和表征候选基因，并确定哪个基因是负责SEDT。将使用位置克隆方法、改良的候选基因方法和基因组序列驱动方法分离候选基因。 SEDT基因将通过受影响个体的突变分析进行鉴定和确认。SEDT基因的特征将建立这种骨骼疾病的病因，揭示一个新的和重要的因素，软骨内骨形成，并提供有关软骨生物学的重要见解。