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.

脊椎皮骨骼发育不良（SEDT）是一种X连锁的隐性骨软骨发育不全，其特征是椎骨畸形和主要关节内epiphyses的畸变。 身材矮小和骨关节炎是受影响男性所遭受的主要问题。 SEDT已映射到XP22，但SEDT基因缺陷尚不清楚。 从阿肯色州的大型六代亲属中，SEDT的临床和放射学演变的表征记录了骨骼发育的产后缺陷。 受影响的半合子雄性在出生时具有射线照相正常的椎骨，但在明显异常的内软骨内骨形成后不久，椎骨和毛epiphyses中的不同意的环尖体反映出。椎间盘的退化导致脊柱关节的身高损失和破坏，股骨头和颈部畸形会导致臀部退行性疾病。 在SEDT基因缺陷的这种属性的，杂合的杂志中，强制性载体妇女表现出微妙的异常。 累积放射线学发现表明在基因中发生了干扰，该基因会导致轴向骨骼内的软骨骨形成。 SEDT基因将被鉴定。 特定目标首先使用该六代亲属的链接分析在XP22.2中确认并缩小了候选区域，然后分离并表征候选基因，并确定哪个基因负责SEDT。候选基因将使用位置克隆方法，修饰的候选基因方法和基因组序列驱动方法分离。 SEDT基因将通过对受影响个体的突变分析来识别和确认。 SEDT基因的表征将建立这种骨骼疾病的病因，揭示了内侧软骨骨形成的新重要因素，并提供有关软骨生物学的重要见解。