Ishiko Akira, Masunaga Takuji, Ota Takayuki, Nishikawa Takeji
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
Exp Dermatol. 2004 Apr;13(4):229-33. doi: 10.1111/j.0906-6705.2004.00167.x.
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disease caused by mutations in the gene encoding type VII collagen (COL7A1). The mutations are highly variable and this greatly complicates the study of the genotype-phenotype relationships. To date, three recurrent mutations, specific to Japanese RDEB patients have been reported. By comparing the phenotypes of RDEB patients with different recurrent mutations, the upstream positions of the premature termination codons (PTCs) showed strong correlation with the RDEB clinical disease severity. However, such correlations have not been supported by patients with mutations that were different from these recurrent Japanese patients mutations. In this study, we report a case of RDEB with a very mild clinical phenotype, who was a compound heterozygote harbouring both a recurrent Japanese mutation and a novel deletion mutation resulting in a more upstream PTC. The patient and his mother were shown to have a recurrent donor splice site mutation within intron 81 (6573 + 1G > C), a recurrent Japanese mutation that activates a cryptic donor splicing site and results in a downstream PTC. The patient and his father shared a single-nucleotide deletion within exon 64 (5504delA), which causes a downstream frame shift in five amino acids before creating a PTC. Occurrence of the PTCs in mRNA was confirmed by reverse transcription-polymerase chain reaction (RT)-PCR. The patient's skin showed reduced immunofluorescence staining for COL7A1 and reduced number of abnormal or short anchoring fibrils by electron microscopy. Although the position of the mutation 5504delA PTC was located upstream of the previous mutations reported in combination with the 6573 + 1G > C mutation, the two mutations together give an apparently milder clinical phenotype. Therefore, genotype-phenotype relationships in RDEB cannot be explained purely by the position of PTC.
隐性营养不良型大疱性表皮松解症（RDEB）是一种由编码VII型胶原蛋白（COL7A1）的基因突变引起的遗传性皮肤病。这些突变具有高度变异性，这使得基因型与表型关系的研究变得极为复杂。迄今为止，已报道了三种日本RDEB患者特有的复发性突变。通过比较具有不同复发性突变的RDEB患者的表型，提前终止密码子（PTC）的上游位置与RDEB临床疾病严重程度显示出强烈的相关性。然而，与这些日本复发性患者突变不同的突变患者并未支持这种相关性。在本研究中，我们报告了一例临床表型非常轻微的RDEB病例，该患者为复合杂合子，携带一种日本复发性突变和一种导致更上游PTC的新型缺失突变。该患者及其母亲在内含子81（6573 + 1G > C）中有一个复发性供体剪接位点突变，这是一种日本复发性突变，可激活一个隐蔽的供体剪接位点并导致下游PTC。该患者及其父亲在外显子64（5504delA）中有一个单核苷酸缺失，这会导致五个氨基酸的下游移码，然后产生一个PTC。通过逆转录 - 聚合酶链反应（RT）-PCR证实了mRNA中PTC的存在。患者的皮肤显示COL7A1免疫荧光染色减少，电子显微镜下异常或短锚定原纤维数量减少。尽管5504delA PTC突变的位置位于先前与6573 + 1G > C突变联合报道的突变的上游，但这两个突变共同产生了明显较轻的临床表型。因此，RDEB中的基因型与表型关系不能仅由PTC的位置来解释。
