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）：婴儿皮质肥大 （Caffey氏病）是一种罕见的遗传疾病 骨皮质和髓质狭窄，可以在 X射线。 通常，疼痛的肿胀发生在涉及的骨骼上。 发作 症状仍处于起步阶段，并且在两年之前自发解决 年龄没有残留效果或复发。 这些临床发现表明 在皮质骨生长调节中的暂时性，局部缺陷， 负责任遗传缺陷的识别可能有助于增强 了解皮质骨的生长和维持 理解不佳。 患有这种疾病的家庭的谱系显示常染色体 继承的主要模式。 没有与此相关的遗传缺陷 疾病尚未描述，也没有鉴定出遗传基因座。 这 迄今为止，候选人已经从26个成员那里获得了DNA样本（有19个成员，1个 一个大型法国 - 加拿大人的假定未受影响和6个无关的配偶） 伴有婴儿皮质的常染色体显性遗传 Hypystosis，他建议使用链接研究来确定基因 负责这种疾病的基因座。 一旦确定了这个基因座， 与该疾病有关的基因组区域将由染色体界定 研究中的家庭中的跨越事件以及其他家庭 患有相同的疾病。 利用通过 人类基因组项目，该链接区域内包含的基因将是 将选择确定的和候选基因。 候选人的编码区域 基因将在受影响个体的基因组DNA中进行测序（家族和 将研究零星病例）寻找可能是 负责这种疾病。 南印迹分析也将进行 搜索DNA删除。 一旦删除或突变（Caffey突变）是 候选人将在所有受影响的大型亲属的成员中确定 在其他（较小）的同一基因中搜索与其他基因的突变 Caffey病和零星的病例，他将排除存在 来自众多健康个体的DNA突变。 随后， 候选者将分离鼠cDNA同源物，如果这是一个新的基因， 将研究北部基因的时间和空间表达方式 印迹分析。 野生型蛋白的功能，沿着 蛋白质功能上的咖啡质突变将使用视野进行研究 系统。 最终，鉴定可能参与的蛋白质 调节皮质骨的厚度和直径可能会提供重要的 对调节骨形成和重塑的新见解，并且可能 为旨在降低风险的药物提供了新的目标 断裂。