Rosado Consolación, Bueno Elena, Felipe Carmen, González-Sarmiento Rogelio
Department of Medicine, Molecular Medicine Unit, University of Salamanca Salamanca, Spain ; Department of Nephrology, Ávila Hospital Ávila, Spain.
Department of Medicine, Molecular Medicine Unit, University of Salamanca Salamanca, Spain ; IBSAL and IBMCC, University of Salamanca, CSIC and SACYL Salamanca, Spain.
Int J Mol Epidemiol Genet. 2014 Dec 15;5(4):177-84. eCollection 2014.
Autosomal forms of Alport syndrome represent 20% of all patients (15% recessive and 5% dominant). They are caused by mutations in the COL4A3 and COL4A4 genes, which encode a-3 and a-4 collagen IV chains of the glomerular basement membrane, cochlea and eye. Thin basement membrane nephropathy may affect up to 1% of the population. The pattern of inheritance in the 40% of cases is the same as autosomal dominant Alport syndrome: heterozygous mutations in these genes. The aim of this study is to detect new pathogenic mutations in the COL4A4 gene in the patients previously diagnosed with autosomal Alport syndrome and thin basement membrane nephropathy in our hospital.
We conducted a clinical and genetic study in eleven patients belonging to six unrelated families with aforementioned clinical symptoms and a negative study of COL4A3 gene. The molecular study was made by conformation of sensitive gel electrophoresis (CSGE) and direct sequencing of the fragments that show an altered electrophoretic migration pattern.
We found two pathogenic mutations, not yet described: IVS3 + 1G > C is a replacement of Guanine to Cytosine in position +1 of intron 3, in the splicing region, which leads to a pathogenic mutation. c.4267C > T; p.P1423S is a missense mutation, also considered pathogenic. We also found seven new polymorphisms.
We describe two new pathogenic mutations, responsible for autosomal dominant Alport syndrome. The other families of the study were undiagnosed owing to problems in the method employed and the possibility of mutations in other genes, giving rise to other diseases with similar symptoms.
常染色体形式的Alport综合征占所有患者的20%（15%为隐性，5%为显性）。它们由COL4A3和COL4A4基因的突变引起，这两个基因编码肾小球基底膜、耳蜗和眼睛的α-3和α-4胶原蛋白IV链。薄基底膜肾病可能影响高达1%的人群。40%的病例的遗传模式与常染色体显性Alport综合征相同：这些基因中的杂合突变。本研究的目的是在我院先前诊断为常染色体Alport综合征和薄基底膜肾病的患者中检测COL4A4基因的新致病突变。
我们对11名来自6个无亲缘关系家庭的患者进行了临床和遗传学研究，这些患者有上述临床症状且COL4A3基因研究为阴性。分子研究通过敏感凝胶电泳构象（CSGE）和对显示电泳迁移模式改变的片段进行直接测序来进行。
我们发现了两个尚未描述的致病突变：IVS3 + 1G > C是内含子3第+1位的鸟嘌呤被胞嘧啶取代，位于剪接区域，导致致病突变。c.4267C > T；p.P1423S是一个错义突变，也被认为是致病的。我们还发现了7个新的多态性。
我们描述了两个导致常染色体显性Alport综合征的新致病突变。由于所采用方法的问题以及其他基因发生突变的可能性，本研究中的其他家庭未得到诊断，从而导致出现具有相似症状的其他疾病。
