Kon A, Pulkkinen L, Hara M, Tamai K, Tagami H, Hashimoto I, Uitto J
Department of Dermatology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Philadelphia 19107, PA. USA.
Hum Mutat. 1998;12(4):288. doi: 10.1002/(SICI)1098-1004(1998)12:4<280::AID-HUMU11>3.0.CO;2-V.
Herlitz junctional epidermolysis bullosa (H-JEB; OMIM #226700) is a lethal, autosomal recessive blistering disorder characterized by fragility of the skin and other specialized epithelia. Previously, mutations in the laminin 5 genes (LAMA3, LAMB3, and LAMC2) have been disclosed, most of them in LAMB3. In this study, we have examined the genetic basis of H-JEB in three families utilizing heteroduplex analysis and automated nucleotide sequencing. In one family, the proband was compound heterozygote for previously unpublished LAMB3 mutations, 1482delC and W95X. In two other families, the probands were found to be homozygous for novel nonsense mutations C553X and K822X in the LAMC2 gene. These mutations result in premature termination codons and predict truncation of the corresponding polypeptides. Also, during the search of laminin 5 mutations, 18 LAMB3 and LAMC2 polymorphisms were discovered, 9 of them being previously undescribed. Delineation of novel homozygous nonsense mutations in the LAMB3 and LAMC2 genes, with previous demonstrations of LAMA3 mutations, re-emphasizes the concept that stop codon mutations in both alleles of any of the three laminin 5 genes result in the severe H-JEB phenotype.
赫利茨交界型大疱性表皮松解症（H-JEB；OMIM #226700）是一种致死性常染色体隐性遗传性水疱病，其特征为皮肤和其他特殊上皮组织的脆弱性。此前，已发现层粘连蛋白5基因（LAMA3、LAMB3和LAMC2）存在突变，其中大多数位于LAMB3基因。在本研究中，我们利用异源双链分析和自动核苷酸测序技术，对三个家系中H-JEB的遗传基础进行了研究。在一个家系中，先证者是之前未发表的LAMB3突变1482delC和W95X的复合杂合子。在另外两个家系中，先证者被发现是LAMC2基因中新的无义突变C553X和K822X的纯合子。这些突变导致提前终止密码子出现，并预示相应多肽会被截短。此外，在搜索层粘连蛋白5突变的过程中，发现了18个LAMB3和LAMC2多态性位点，其中9个是之前未描述过的。LAMB3和LAMC2基因中新的纯合无义突变的确定，以及之前所证实的LAMA3突变，再次强调了这样一个概念：层粘连蛋白5三个基因中任何一个基因的两个等位基因发生终止密码子突变都会导致严重的H-JEB表型。
