MOLECULAR GENETICS OF PSEUDOXANTHOMAS ELASTICUM

弹性假黄瘤的分子遗传学

• 批准号: 6235816
• 负责人: KLAUS LINDPAINTNER
• 金额: $ 6.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235816
• 关键词: artificial chromosomes; clinical research; disease /disorder etiology; family genetics; genetic mapping; human genetic material tag; human subject; nucleic acid sequence; pseudoxanthoma elasticum

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.

弹性假黄瘤（PXE）是一种典型的遗传性疾病