Gene Defect in Infantile Cortical Hyperostosis

婴儿皮质骨质增生症的基因缺陷

• 批准号: 6882374
• 负责人: ROBERT C GENSURE
• 金额: $ 9.01万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 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/6882374
• 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)：婴儿皮质骨质增生症 (卡菲氏病)是一种罕见的遗传性疾病，伴有局限性增厚 骨皮质和髓质狭窄，可在 X射线。通常，疼痛的肿胀发生在受累的骨骼上。开始于 症状处于婴儿期，在两年前出现自发缓解。 年龄，无后遗症或复发。这些临床发现表明 皮质骨生长调节中的暂时性、局限性缺陷，以及 识别负有责任的基因缺陷可能有助于加强 了解皮质骨的生长和维持，这是残留的 人们对此知之甚少。这种疾病家族的家系显示为常染色体 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。这个 候选人迄今已从26名成员(19名受影响，1名 推定不受影响，以及6名无亲属关系的配偶) 婴儿皮质常染色体显性遗传一家系 他建议使用连锁研究来确定基因 导致这种疾病的基因座。一旦确定了这个基因座， 与疾病相关的基因组区域将由染色体来划定 正在研究的家庭中的交叉事件，以及潜在的其他家庭 患有同样的疾病。利用可通过 人类基因组计划，包含在这个连接区域内的基因将被 确定的和候选的基因将被选择。候选基因的编码区 基因将在受影响个人(家族性和家族性)的基因组DNA中进行测序 将对零星病例进行研究)，以寻找可能是 对这种混乱负有责任。还将进行Southern杂交分析 来搜索DNA缺失。一旦缺失或突变(Caffey突变) 在所有受影响的大家族成员中，候选人将 在其他(较小的)家族中寻找相同基因的突变 卡菲氏病和零星病例，他将排除 来自许多健康个体的DNA的这种突变。随后， 候选人将分离出小鼠的cdna同源基因，如果这是一个新基因， 将由Northern研究该基因的时空表达模式 印迹分析。野生型蛋白的功能，以及 Caffey突变对蛋白质功能的影响将在体外进行研究 系统。归根结底，鉴定一种可能参与 调节皮质骨的厚度和直径可能会提供重要的 对骨形成和重塑调节的新见解，并可能 为药物制剂提供一个新的目标，旨在降低 骨折。