Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa
Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa
复制标题
DOI：
10.1093/hmg/5.2.231
复制
发表时间：
1996-02-01
影响因子：
3.5
通讯作者：
Christiano, AM
中科院分区：
文献类型：
--
作者：
Kivirikko, S;McGrath, JA;Christiano, AM
Herlitz型交界性大疱性表皮松解症(H-Jeb)是一种影响皮肤和粘膜的严重起泡性疾病，层粘连蛋白5已被认为是大多数H-Jeb患者的候选基因/蛋白系统。在本研究中，我们检测了14个H-Jeb家系的LAMB3基因突变，每个家系的两个等位基因都出现了提前终止密码子突变，有趣的是，在突变的LAMB3等位基因中发现了两个重复的突变R42X和R635X，这些无义突变发生在CPG核苷酸序列上，提示5-甲基胞嘧啶对胸腺嘧啶的高度突变。进一步的证据表明，R42X和R635X代表突变热点，首先，通过单倍型分析证实了R635X在两个不同遗传背景的纯合子个体中的遗传。此外，在一个家庭中，R42X被证明遗传在缺乏这种突变的母体等位基因上，这表明它是由母体生殖系突变引起的。阐明这两个热点突变将有助于筛查其他JEB患者的潜在突变。
The Herlitz type of junctional epidermolysis bullosa (H-JEB) is a severe blistering disease affecting the skin and mucous membranes, and laminin 5 has been implicated as the candidate gene/protein system for most patients with H-JEB, In this study, we have examined a cohort of 14 families with H-JEB for mutations in the LAMB3 gene, Premature termination codon mutations were delineated in both alleles of each proband in all pedigrees, Interestingly, two recurrent mutations, R42X and R635X, were noted in over 50% of the mutant LAMB3 alleles, These nonsense mutations occurred at CPG dinucleotide sequences, suggesting hypermutability of 5-methylcytosine to thymine. Additional evidence suggested that R42X and R635X represent mutational hotspots, First, the inheritance of R635X in a homozygous individual on two different genetic backgrounds was demonstrated by haplotype analysis. Furthermore, in one family, R42X was shown to be inherited on the maternal allele which lacked this mutation, suggesting that it arose as a result of maternal germline mutation. Elucidation of these two hotspot mutations will facilitate screening of additional JEB patients for the underlying mutations.