Gene Defect in Infantile Cortical Hyperostosis

婴儿皮质骨质增生症的基因缺陷

• 批准号: 6729147
• 负责人: ROBERT C GENSURE
• 金额: $ 11.98万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729147
• 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（由考生提供）：婴儿皮质骨质增生症 （卡菲氏病）是一种罕见的遗传性疾病，伴有局部增厚 骨皮质和髓质狭窄，这在骨皮质和髓质狭窄中表现得相当明显 X 射线。 通常，受影响的骨头会出现疼痛肿胀。 发病 症状处于婴儿期，两年前会自然消退 无残留影响或复发的年龄。 这些临床发现表明 皮质骨生长调节中的暂时性局部缺陷，以及 识别相关的遗传缺陷可能有助于增强 对皮质骨的生长和维护的了解，仍然存在 不太了解。 患有这种疾病的家族谱系显示常染色体遗传 遗传的主导模式。 没有与此相关的遗传缺陷 疾病尚未被描述，也尚未确定遗传位点。 这 候选人迄今已获得 26 名成员的 DNA 样本（19 名受影响者、1 名成员） 一名大型法裔加拿大人（假定未受影响，以及 6 位无亲属关系的配偶） 具有婴儿皮质常染色体显性遗传的亲属 骨质增生，他建议利用连锁研究来确定基因 导致这种疾病的位点。 一旦确定了该位点， 与疾病相关的基因组区域将由染色体界定 所研究的家庭以及其他家庭中可能存在的交叉事件 患有同样的疾病。 利用可通过以下途径获得的序列信息 人类基因组计划，该链接区域中包含的基因将被 确定并选择候选基因。 候选区域的编码 将对受影响个体（家族和个体）的基因组 DNA 中的基因进行测序。 将研究散发病例）以寻找可能的突变 对这种紊乱负责。 还将进行 Southern blot 分析 寻找 DNA 缺失。 一旦发生删除或突变（Caffey 突变） 在所有受影响的大亲属成员中确定后，候选人将 在其他（较小的）亲属中搜索相同基因的突变 卡菲氏病和散发病例，他会排除以下情况的存在 这种 DNA 突变来自许多健康个体。 随后， 候选者将分离出小鼠 cDNA 同源物，如果这是一个新基因， 将研究北方基因表达的时间和空间模式 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，将使用体外研究 系统。 最终，鉴定出可能参与的蛋白质 调节皮质骨的厚度和直径可能提供重要的 对骨形成和重塑调节的新见解，可能 为旨在降低风险的药剂提供新的目标 骨折。

项目成果

A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders.

婴儿皮质骨质增生症（卡菲病）中的一种新的 COL1A1 突变扩大了胶原蛋白相关疾病的范围。

• DOI: 10.1172/jci22760
• 发表时间: 2005
• 期刊: The Journal of clinical investigation
• 作者: Gensure,RobertC;Mäkitie,Outi;Barclay,Catherine;Chan,Catherine;Depalma,StevenR;Bastepe,Murat;Abuzahra,Hilal;Couper,Richard;Mundlos,Stefan;Sillence,David;AlaKokko,Leena;Seidman,JonathanG;Cole,WilliamG;Jüppner,Harald
• 通讯作者: Jüppner,Harald