GENETICS OF FAMILIAL HYPOCALCIURIC HYPERCALCEMIA

家族性低尿钙高钙血症（FHH）是一种 以常染色体显性方式遗传，受影响的个体 血清钙浓度异常高， 尿钙含量过低 我们假设 患有这种疾病的受影响个体以异常的方式调节钙。 时尚和理解钙的这种扰动机制 监管将提供重要的信息， 和钙稳态的正常机制。 的模式 这种疾病遗传性表明单个基因的突变 负责FHH，我们建议通过分子生物学方法鉴定该基因， 基因技术已经被用来识别其他基因， 突变会导致疾病 虽然这些技术需要大量的 努力，识别精确基因和突变的好处 让这种努力变得有价值 的 所提出的研究的长期目标是鉴定 在FHH患者中发生突变，并确定 FHH到另一种钙调节障碍，新生儿重度 甲状旁腺功能亢进（NSHPT）。 我们将采取以下方法来识别突变 负责FHH。 1)确定FHH是否为遗传异质性 或同质性疾病，并细化FHH区域中的遗传图谱; 2)细化FHH-1区域的物理图; 3）搜索FHH区域 4）鉴定候选基因， 确定它们是否在FHH受试者中突变;以及5）确定NSHPT是否 FHH-1基因座的纯合缺陷。

Familial hypocalciuric hypercalcaemia (FHH) is a disorder that is inherited in an autosomal dominant fashion in which affected individuals have abnormally high concentrations of serum calcium and excrete inappropriately low amounts of urinary calcium. We hypothesize that affected individuals with this disorder regulate calcium in an abnormal fashion and that understanding this perturbed mechanism of calcium regulation will provide important information both about this disorder and the normal mechanism of calcium homeostasis. The patterns of inheritance of this disorder suggest that a mutation(s) in a single gene is responsible for FHH, and we propose to identify this gene by molecular genetic techniques that have been used to identify other genes that when mutated cause disease. Although these techniques require significant effort, the benefits of identifying the precise gene and the mutation(s) responsible for a particular disorder make this effort worthwhile. The long term goals of the proposed studies are to identify the gene(s) that is mutated in FHH patients and to determine the genetic relationship of FHH to another disorder of calcium regulation, neonatal severe hyperparathyroidism (NSHPT). We will take the following approaches to identify the mutation(s) responsible for FHH. 1) Determine if FHH is a genetically heterogeneous or homogeneous disorder and refine the genetic map in the FHH region(s); 2) Refine the physical map in the FHH-1 region; 3) Search the FHH region of chromosome 3 for gene segments; 4) Identify candidate genes and determine if they are mutated in FHH subjects; and 5) Determine if NSHPT results from homozygous deficiencies at the FHH-1 locus.