Gene Defect in Infantile Cortical Hyperostosis

婴儿皮质骨质增生症的基因缺陷

• 批准号: 6420082
• 负责人: ROBERT C GENSURE
• 金额: $ 12.46万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6420082
• 关键词: Canada; European; animal genetic material tag; bone development disorder; complementary DNA; family genetics; gene expression; gene mutation; genetic disorder; human subject; hypertrophy; linkage mapping; northern blottings; nucleic acid sequence; patient oriented research; protein structure function; southern blotting

DESCRIPTION (provided by candidate): Infantile cortical hyperostosis (Caffey's disease) is a rare genetic disorder with localized thickening of the bone cortex and medullary stenosis, which can appear quite prominently on x-ray. Often, painful swelling occurs over the involved bones. Onset of symptoms is in infancy, and spontaneous resolution occurs before two years of age with no residual effects or recurrences. These clinical findings suggest a transitory, localized defect in the regulation of cortical bone growth, and identification of the responsible genetic defect may serve to enhance the understanding of the growth and maintenance of cortical bone, which remains poorly understood. Pedigrees of families with this disorder show an autosomal dominant pattern of inheritance. No genetic defect associated with this disorder has yet been described, nor has a genetic locus been identified. The candidate has thus far obtained DNA samples from 26 members (19 affected, 1 presumed unaffected, and 6 unrelated spouses) of a large French-Canadian kindred with autosomal dominant inheritance of infantile cortical hyperostosis, and he proposes to use linkage studies to determine the gene locus responsible for this disorder. Once this locus has been identified, the genomic region which is linked to the disease will be delimited by chromosomal crossing-over events in family under study and, potentially, other families with the same disorder. Utilizing sequence information available through the Human Genome Project, genes contained within this linked region will be identified and candidate genes will be selected. Coding regions of candidate genes will be sequenced in genomic DNA from affected individuals (familial and sporadic cases will be studied) to search for mutations which may be responsible for the disorder. Southern blot analyses will also be performed to search for DNA deletions. Once a deletion or mutation (Caffey mutation) is identified in all affected members of the large kindred, the candidate will search for mutations in the same gene in other (smaller) kindreds with Caffey's disease and in sporadic cases, and he will exclude the presence of this mutation in DNA from numerous healthy individuals. Subsequently, the candidate will isolate the murine cDNA homolog and, if this is a novel gene, will study the gene's temporal and spatial patterns of expression by Northern blot analysis. The function of the wild-type protein, along the effects of the Caffey mutation on protein function, will be studied using in-vitro systems. Ultimately, the identification of a protein which may be involved in regulating the thickness and diameter of cortical bone might provide important new insights into the regulation of bone formation and remodeling, and may provide a new target for pharmaceutical agents aimed at reducing the risk of fractures.

描述（由候选人提供）：婴儿皮质骨肥大 （卡菲病）是一种罕见的遗传性疾病， 骨皮质和骨髓狭窄，这可能会出现相当突出， x光片 通常，疼痛的肿胀发生在所涉及的骨头上。 发作 症状是在婴儿期，自发解决发生在两年前， 无残留影响或复发。 这些临床发现表明 皮质骨生长调节中的暂时性局部缺陷，和 鉴定负责的遗传缺陷可能有助于提高 了解皮质骨的生长和维持， 不太了解。 家系与这种疾病显示常染色体 显性遗传模式。 没有与此相关的遗传缺陷 疾病尚未被描述，也没有确定遗传位点。 的 迄今为止，候选人已从26名成员（19名受影响，1名 假定未受影响，和6个无关的配偶）的一个大法裔加拿大人 常染色体显性遗传婴儿皮质 骨质增生，他建议使用连锁研究来确定基因 导致这种疾病的基因位点 一旦确定了这个位点， 与疾病连锁的基因组区域将由染色体 研究中的家族和潜在的其他家族中的交叉事件 同样的紊乱。 利用可通过以下途径获得的序列信息： 人类基因组计划，基因包含在这个连接的区域将是 将识别和选择候选基因。 候选人的编码区 将对来自受影响个体的基因组DNA中的基因进行测序（家族性和 将研究散发病例），以寻找可能 负责混乱。 还将进行Southern印迹分析 寻找DNA缺失 一旦缺失或突变（Caffey突变）， 在大型亲属的所有受影响成员中确定，候选人将 在其他（较小）激酶中寻找相同基因的突变， 他将排除存在的 这种突变来自于许多健康个体的DNA。 随后 候选者将分离鼠cDNA同源物，如果这是新基因， 将通过北方基因组研究该基因表达的时间和空间模式， 印迹分析 野生型蛋白的功能，沿着 Caffey突变对蛋白质功能的影响，将使用体外研究 系统. 最终，鉴定出可能参与 调节皮质骨的厚度和直径可能提供重要的 对骨形成和重塑的调节有了新的认识， 为药剂提供了一个新的靶点， 骨折