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.

迟发性脊柱骨骺发育不良(SEDT)是一种X连锁的隐性骨软骨发育不良症，主要表现为椎体畸形和大关节内骨骺变形。身材矮小和骨关节炎是受影响男性的主要问题。SEDT基因已被定位于Xp22，但SEDT基因缺陷尚不清楚。来自阿肯色州的一个大型六代家庭的SEDT的临床和放射学演变的特征证明了骨骼发育的出生后缺陷。受影响的偏侧男性在出生时椎体X线片正常，但不久就表现出异常的软骨内骨形成，反映为椎骨中看不见的环状隆起和错位的骨痂。椎间盘退变导致身高下降和脊柱小关节破坏，股骨头和颈部畸形导致髋关节退行性疾病。这个家族中的专职携带者妇女，SEDT基因缺陷的杂合子，表现出微妙的异常。累积的放射学发现表明，主要在中轴骨中形成软骨内骨的基因存在障碍。SEDT基因将被鉴定出来。针对Xp22.2的特定目的，首先对该六代家系进行连锁分析，确定Xp22.2的候选区域，然后分离和鉴定候选基因，确定哪个基因是SEDT的致病基因。候选基因将使用位置克隆方法、改进的候选基因方法和基因组序列驱动方法来分离。SEDT基因将通过对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。