Clinical symptoms and molecular basis of group A xeroderma pigmentosum

A组着色性干皮病的临床症状和分子基础

基本信息

批准号：
06454309
负责人：
TAMAI Hiroshi
金额：
$ 2.24万
依托单位：
Osaka Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06454309/
关键词：
Xeroderma pigmentosum DNA nucleotide excision repair A群色素性乾皮症 DNA修復蛋白質 XPA蛋白質 ERCC1蛋白質 yeast two-hybrid system E-cluster region フィルターバインデイングアッセ-DNA結合能 DNA修復活性酸素消去酵素 XPAC蛋白 RNA解析 DNA診断

项目摘要

The molecular basis of group A xcroderma pingmentosum (XP) was investigated by Southern blot analysis of genomic DNA for allelic heterogeneity in group A XP and comparison of clinical symptoms and severity of neurological complications. As previously reported, two group A XP patients (XP-YK and XP-HH) with mild skin lesions and minimal neurological abnormalities had different mutations, one was a homozygote for the nonsense mutation of exon 6 (XP'-YK), while the other was a compound heterozygote for the splicing mutation of intron 3 and the nonsense mutation of exon 6 (XP-HH). The present study revealed that one typical group A XP patient with severe skin lesions and severe neurological complications also was a compound heterozygote for the splicing mutation of intron 3 and the nonsense mutation of exon 6, thus suggesting the nonsense mutation of exon 6 is not always associated with mild skin lesions nor mild neurological manifestations. Further investigation of the sensitivity to UV radiation of fibroblasts from two atypical group A XP patients (XP-YK and XP-HH) with mild skin lesions and minimal neurological abnormalities showed intermediate post-UV colony-forming ability between that of typical group A and group C XP patients. These results suggest that DNA abnormalities are not always consistent with the severity of clinical symptoms, and that mild clinical symptoms may be explained by the residual ability of the cells to repair UV-damaged DNA.

通过对 A 组 XP 的基因组 DNA 进行 Southern blot 分析，了解 A 组 XP 的等位基因异质性，并比较临床症状和神经系统并发症的严重程度，研究了 A 组 XP 的分子基础。正如之前报道的，两组A组XP患者（XP-YK和XP-HH）具有轻微的皮肤损害和轻微的神经系统异常，具有不同的突变，其中一位是外显子6（XP'-YK）无义突变的纯合子，而另一位是外显子6（XP'-YK）无义突变的纯合子。另一种是内含子3剪接突变和外显子6无义突变（XP-HH）的复合杂合子。本研究发现，一名典型的伴有严重皮肤损伤和严重神经系统并发症的A组XP患者也是内含子3剪接突变和外显子6无义突变的复合杂合子，因此表明外显子6无义突变并不总是存在。伴有轻度皮肤病变或轻度神经系统表现。对两名具有轻度皮肤损伤和最小神经系统异常的非典型 A 组 XP 患者（XP-YK 和 XP-HH）的成纤维细胞对紫外线辐射的敏感性的进一步研究显示，紫外线后集落形成能力介于典型 A 组和C组XP患者。这些结果表明，DNA 异常并不总是与临床症状的严重程度一致，轻微的临床症状可能是由于细胞修复紫外线损伤 DNA 的残余能力所致。