Basic Research Department, Epithelial Biomedicine Division, Regenerative Medicine Unit, CIEMAT-CIBERER U714, Av. Complutense 22, 28040 Madrid, Spain.
Br J Dermatol. 2010 Jul;163(1):155-61. doi: 10.1111/j.1365-2133.2010.09713.x. Epub 2010 Feb 22.
Dystrophic epidermolysis bullosa (DEB) is a genodermatosis caused by mutations in COL7A1. The clinical manifestations are highly variable from nail dystrophy to life-threatening blistering, making early molecular diagnosis and prognosis of utmost importance for the affected families. Mutation identification is mandatory for prenatal testing.
To conduct the first mutational analysis of COL7A1 in a Spanish cohort, to assess mutation consequences at protein/mRNA level and to establish genotype-phenotype correlations.
Forty-nine Spanish patients with DEB were studied. Antigen mapping was performed on patient skin biopsies. COL7A1 mutation screening in genomic DNA was performed by polymerase chain reaction (PCR) and direct sequencing. Mutation consequences were determined by reverse transcriptase-PCR.
Eight patients belonged to three unrelated families with dominant DEB. Forty-one were affected with recessive DEB (RDEB). Specifically, 27 displayed the severe generalized subtype, eight the other generalized subtype and six a localized phenotype (two pretibial, three acral and one inversa). Thirty-five mutations were identified, 20 of which are novel. The pathogenic mutation c.6527insC accounted for 46.3% of Spanish RDEB alleles. A consistent genotype-phenotype correlation was established.
Although the COL7A1 database indicates that most DEB mutations are family specific, the pathogenic mutation c.6527insC was highly recurrent in our cohort. This level of recurrence for a single genetic defect has never previously been reported for COL7A1. Our findings are essential to the clinicians caring for patients with DEB in Spain and in the large population of Spanish descendants in Latin America. They also provide geneticists a molecular clue for a priority mutation screening strategy.
营养不良型大疱性表皮松解症（DEB）是一种由 COL7A1 基因突变引起的遗传性皮肤病。其临床表现从指甲营养不良到危及生命的水疱，差异极大，因此对受累家庭而言，早期进行分子诊断和预后至关重要。突变鉴定对于产前检测是必需的。
对西班牙患者队列中的 COL7A1 进行首次突变分析，评估蛋白/信使 RNA 水平的突变后果，并建立基因型-表型相关性。
对 49 例 DEB 西班牙患者进行研究。对患者皮肤活检标本进行抗原定位。通过聚合酶链反应（PCR）和直接测序对基因组 DNA 中的 COL7A1 突变进行筛选。通过逆转录-PCR 确定突变后果。
8 例患者属于三个无血缘关系的显性 DEB 家系。41 例为隐性 DEB（RDEB）患者。具体而言，27 例为严重的全身性亚型，8 例为其他全身性亚型，6 例为局限性表型（2 例小腿前侧、3 例肢端、1 例逆向）。共发现 35 种突变，其中 20 种为新突变。致病性突变 c.6527insC 占西班牙 RDEB 等位基因的 46.3%。建立了一致的基因型-表型相关性。
尽管 COL7A1 数据库表明大多数 DEB 突变是家族特异性的，但在我们的队列中，致病性突变 c.6527insC 高度重复。这种单一遗传缺陷的重复率以前从未在 COL7A1 中报道过。我们的研究结果对于西班牙 DEB 患者的临床医生以及拉丁美洲大量西班牙裔后裔的遗传学家都至关重要。它们还为遗传学家提供了一个优先进行突变筛选策略的分子线索。
