MOLECULAR GENETICS OF PSEUDOXANTHOMAS ELASTICUM

弹性假黄瘤(PXE)是一种经典的遗传性 以进行性为特征的弹性组织紊乱 弹力纤维钙化的病理组织学研究 外表。PXE的临床表现通常涉及 皮肤、眼睛和心血管系统，导致皮肤损伤， 视力下降，以及血管疾病。这种疾病是遗传性的 主要表现为常染色体隐性遗传，较少表现为常染色体 具有高外显性的显性性状；估计患病率为1% 7万到10万。之前未能将这种疾病与任何 几个候选基因促使我们进行了全基因组筛选， 具有两个或更多受影响兄弟姐妹的38个家庭的集合，使用 等位基因共享算法，随后是高分辨率映射和 隐性遗传和显性遗传的常规连锁算法分析 家人。 在16号染色体的短臂上发现了过度的等位基因共享，并且 通过最大似然连锁分析，确定了疾病的位置 位于染色体16p13.1上3.0 cM区域的隐性家系 最高两分的LOD得分为19.0。在优势家系中的连锁 最大两分Lod评分为3.6分，观察结果相同 到目前为止还没有任何候选基因的区域。我们预测 同一疾病基因不同变异的等位基因异质性 位于染色体16p13.1上，解释了隐性和显性 PXE的形式。 目前已经耗尽了进一步罚款的遗传资源- 基因作图，我们建议追求以下具体目标 找到致病基因的合乎逻辑的步骤： (I)在已确定的区域组装YAC/BAC/PAC/COSMID重叠群。 (Ii)产生高分辨率、有针对性的标记并对基因进行精细定位 直到信息量最大的减数分裂耗尽； (Iii)在如此确定的染色体中搜索表达序列 目标区，使用几种相辅相成的方法，如直接 筛选基因的选择和外显子捕获。 该项目的成功完成将使 疾病基因携带者的分子遗传学诊断，并代表 了解疾病的机制和 开发有针对性的治疗方法。

Pseudoxanthoma elasticum (PXE) is a classically described inherited disorder of the elastic tissue characterized by progressive calcification of elastic fibers with a pathognomonic histological appearance. The clinical manifestations of PXE typically involve the skin, the eye, and the cardiovascular system, resulting in skin lesions, decreased vision, and vascular disease. The disorder is inherited mainly as an autosomal recessive, and less commonly as an autosomal dominant trait with high penetrance; its estimated prevalence is 1 in 70,000 - 100,000. Previous failure to link the disease to any of several candidate genes prompted us to conduct a genome-wide screen, on a collection of 38 families with 2 or more affected siblings, using allele-sharing algorithms, followed by high-resolution mapping and analysis by conventional linkage algorithms in recessive and dominant families. Excess allele-sharing was found on the short arm of chromosome 16, and confirmed by maximum-likelihood linkage analysis, localizing the disease gene in recessive families to a 3.0 cM area on chromosome 16p13.1 with a maximum two-point lod score of 19.0. In dominant families linkage with a maximum two-point lod score of 3.6 was observed to the same region that is so far devoid of any candidate genes. We predict that allelic heterogeneity with different variants of a single disease gene that resides on chromosome 16p13.1 accounts for recessive and dominant forms of PXE. Having presently exhausted the genetic resources for further fine- mapping of the gene, we propose to pursue the following specific aims as logical steps toward finding the causative gene: (i) to assemble YAC/BAC/PAC/cosmid contigs across the region identified. (ii) to generate high resolution, targeted markers and fine-map the gene until exhaustion of informative meioses; (iii) to search for expressed sequences in the so identified chromosomal target zone, using several complementary approaches, such as direct screen cDNA selection and exon trapping. The successful completion of this project will allow the development of molecular genetic diagnostics for disease gene carriers, and represents the first step towards understanding of the disease mechanism and the development of a targeted therapeutic approach.