Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa
Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa
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DOI：
10.1111/j.1365-2230.2004.01660.x
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发表时间：
2005-01-01
影响因子：
4.1
通讯作者：
McGrath, JA
中科院分区：
文献类型：
--
作者：
Fassihi, H;Wessagowit, V;McGrath, JA
赫利茨交界性大疱性表皮松解症 (JEB) 是一种常染色体隐性遗传性大疱性机械性疾病，由编码基底膜成分层粘连蛋白 5 的基因发生功能丧失突变所致。通常，LAMA3、LAMB3 或 LAMC2 基因的两个等位基因上都存在移码、剪接位点或无义突变，受影响的个体从父母双方遗传一个突变等位基因。在本报告中，我们描述了一名 Herlitz JEB 患者，该患者的 DNA 分析显示 LAMB3 中反复出现的无义突变 R635X 具有纯合性，该突变位于染色体 1q32.2 上。然而，对父母DNA的筛查显示，虽然患者的父亲是该突变的杂合携带者，但母亲的DNA仅显示野生型序列。随后使用跨越 1 号染色体的 13 个微卫星标记进行的基因型分析显示，受影响的孩子对于所测试的整个系列标记都是纯合的，并且所有等位基因都源自父亲。这些结果表明，该患者的 Herlitz JEB 表型是由于 1 号染色体完全父本二倍体和突变 LAMB3 基因位点纯合性降低所致。这是 Herlitz JEB 中描述的第四例单亲二倍体，但它代表了第一个 1 号染色体完全父本二倍体且 LAMB3 基因发生致病性突变的例子。这些发现对于 JEB 突变筛查和遗传咨询具有重要意义。
Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mechanobullous disorder that results from loss-of-function mutations in the genes encoding the basement membrane component, laminin 5. Typically, there are frameshift, splice site or nonsense mutations on both alleles of either the LAMA3, LAMB3 or LAMC2 genes, with affected individuals inheriting one mutated allele from each parent. In this report, we describe a patient with Herlitz JEB in whom DNA analysis revealed homozygosity for the recurrent nonsense mutation R635X in LAMB3, located on chromosome 1q32.2. However, screening of parental DNA showed that although the patient's father was a heterozygous carrier of this mutation, the mother's DNA showed only wild-type sequence. Subsequent genotype analysis using 13 microsatellite markers spanning chromosome 1 revealed that the affected child was homozygous for the entire series of markers tested and that all of the alleles originated from the father. These results indicate that the Herlitz JEB phenotype in this patient is due to complete paternal isodisomy of chromosome 1 and reduction to homozygosity of the mutant LAMB3 gene locus. This is the fourth case of uniparental disomy to be described in Herlitz JEB, but it represents the first example of complete paternal isodisomy for chromosome 1 with a pathogenic mutation in the LAMB3 gene. These findings have important implications for mutation screening in JEB and for genetic counselling.