ALPORT SYNDROME GENETICS AND MUTATION DETECTION

描述：Col4A5基因缺陷，该基因编码不同的 基底膜胶原α5(V)，最近在 阿尔波特综合征(AS)，一种遗传性进行性肾小球肾炎。这个 疾病表现出明显的表型变异，类似于成骨 不完美，COL1A1和COL1A2的各种缺陷导致骨骼 具有非常广泛的表型严重性的脆弱性。在AS中， 疾病根据相关耳聋的严重程度而有所不同， 发病年龄和终末期肾病(需要肾移植 或永久透析疗法)，以及特有的眼睛和 血液异常。听力损失的可变性似乎是由于 Col4A5的等位基因变异，因为两个突变完全存在于 该基因会导致不同程度的耳聋。申请者提议 进行基因研究，以确定是否有任何 Alport家族位于Col4A5以外的一个基因座上。作为协作计划的一部分 经过努力，申请者将检查Col4A5基因的突变情况 缺陷似乎居住在这个位置的家庭。全面 合作者对这些家族的临床特征将是 这些研究将共同构成相互关系的基础 具有可变表型的分子缺陷。确立这一点 相关性将提高治疗性干预的疗效 并有助于更好地理解Col4A5在 基底膜的分子结构，可能暗示了 干预疾病进展过程的手段。这个 还将检查新的Col4A5突变的来源情况 以确定是否有任何重要的风险因素。

DESCRIPTION: Defects in the COL4A5 gene, which encodes the distinct basement membrane collagen alpha5(V), have recently been demonstrated in Alport Syndrome (AS), a hereditary progressive glomerulonephritis. The disease shows substantial phenotypic variation, similar to osteogenesis imperfecta, where various defects in COL1A1 and COL1A2 cause bone fragility with a very wide range of phenotypic severity. In AS, the disease varies with respect to the severity of associated deafness, the age of onset and end-stage renal disease (which requires kidney transplant or permanent dialysis therapy), and the presence of characteristic eye and blood abnormalities. The variability of hearing loss appears to be due to allelic variation at COL4A5, since two mutations which lie entirely within the gene cause deafness of different severities. The applicants propose to perform genetic studies to determine if the genetic defect in any Alport family is at a locus other than COL4A5. As part of a collaborative effort, the applicants will examine the COL4A5 gene for mutation in families where the defect appears to reside at this locus. Comprehensive clinical characterization of these families by collaborators will be conducted and together these studies will form the basis for a correlation of the molecular defects with the variable phenotypes. Establishing this correlation will improve the efficacy of therapeutic intervention in the disease and lead to a better understanding of the role of COL4A5 in the molecular architecture of the basement membrane, perhaps suggesting some means of intervening in the progressive disease process. The circumstances of the origin of new COL4A5 mutations will also be examined to determine if there are any important risk factors.