Longo Ilaria, Scala Elisa, Mari Francesca, Caselli Rossella, Pescucci Chiara, Mencarelli Maria Antonietta, Speciale Caterina, Giani Marisa, Bresin Elena, Caringella Domenica Angela, Borochowitz Zvi-Uri, Siriwardena Komudi, Winship Ingrid, Renieri Alessandra, Meloni Ilaria
Department of Molecular Biology, University of Siena, Italy.
Nephrol Dial Transplant. 2006 Mar;21(3):665-71. doi: 10.1093/ndt/gfi312. Epub 2005 Dec 7.
Alport syndrome (ATS) is a progressive inherited nephropathy characterized by irregular thinning, thickening and splitting of the glomerular basement membrane (GBM) often associated with hearing loss and ocular symptoms. ATS has been shown to be caused by COL4A5 mutations in its X-linked form and by COL4A3 and COL4A4 mutations in its autosomal forms.
Five families with a suspicion of ATS were investigated both from a clinical and molecular point of view. COL4A3 and COL4A4 genes were analysed by DHPLC. Automated sequencing was performed to identify the underlying mutation.
Molecular analysis indicated that in all 5 cases the correct diagnosis was autosomal recessive ATS. In three families in which parental consanguinity clearly pinpointed to autosomal recessive ATS, we found COL4A4 homozygous mutations in two of them and COL4A3 homozygous mutation in the other one. In the remaining two families a differential diagnosis including X-linked ATS, autosomal recessive ATS and thin basement membrane nephropathy was considered. The molecular analysis demonstrated that the probands were genetic compounds for two different mutations in the COL4A4 gene pinpointing to the correct diagnosis of autosomal recessive ATS.
A clinical evaluation of probands and their relatives of the five families carrying mutations in either the COL4A3 or the COL4A4 gene was carried out to underline the natural history of the autosomal recessive ATS. In addition, this paper stresses the complexity of the clinics and genetics of ATS and how a correct diagnosis is based on a combination of: (i) an in-depth clinical investigation; (ii) a detailed formal genetic analysis; (iii) a correct technical choice of the gene to be investigated; (iv) a correct technical choice of the family member to be included in the mutational screening. A correct diagnosis is the basis for an appropriate genetic counselling dealing with both the correct prognosis and the accurate recurrence risk for the patients and family members.
Alport综合征（ATS）是一种进行性遗传性肾病，其特征为肾小球基底膜（GBM）不规则变薄、增厚和分层，常伴有听力丧失和眼部症状。已表明，X连锁型ATS由COL4A5突变引起，常染色体型ATS由COL4A3和COL4A4突变引起。
从临床和分子角度对五个疑似ATS的家庭进行了调查。通过变性高效液相色谱（DHPLC）分析COL4A3和COL4A4基因。进行自动测序以确定潜在突变。
分子分析表明，所有5例病例的正确诊断均为常染色体隐性ATS。在三个父母近亲结婚明确指向常染色体隐性ATS的家庭中，我们在其中两个家庭中发现了COL4A4纯合突变，在另一个家庭中发现了COL4A3纯合突变。在其余两个家庭中，考虑了包括X连锁ATS、常染色体隐性ATS和薄基底膜肾病在内的鉴别诊断。分子分析表明，先证者是COL4A4基因中两种不同突变的遗传复合杂合子，从而明确诊断为常染色体隐性ATS。
对五个携带COL4A3或COL4A4基因突变的家庭的先证者及其亲属进行了临床评估，以强调常染色体隐性ATS的自然病史。此外，本文强调了ATS临床和遗传学的复杂性，以及正确诊断如何基于以下几点的结合：（i）深入的临床调查；（ii）详细的正式遗传分析；（iii）对要研究基因的正确技术选择；（iv）对纳入突变筛查的家庭成员的正确技术选择。正确诊断是进行适当遗传咨询的基础，可为患者及其家庭成员提供正确的预后和准确的复发风险。
