Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
Kidney Int. 2014 May;85(5):1208-13. doi: 10.1038/ki.2013.479. Epub 2013 Dec 4.
X-linked Alport syndrome is caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain (α5(IV)). Complete absence of α5(IV) in the renal basal membrane is considered a pathological characteristic in male patients; however, positive α5(IV) staining has been found in over 20% of patients. We retrospectively studied 52 genetically diagnosed male X-linked Alport syndrome patients to evaluate differences in clinical characteristics and renal outcomes between 15 α5(IV)-positive and 37 α5(IV)-negative patients. Thirteen patients in the α5(IV)-positive group had non-truncating mutations consisting of nine missense mutations, three in-frame deletions, and one splice-site mutation resulting in small in-frame deletions of transcripts. The remaining two showed somatic mutations with mosaicism. Missense mutations in the α5(IV)-positive group were more likely to be located before exon 25 compared with missense mutations in the α5(IV)-negative group. Furthermore, urinary protein levels were significantly lower and the age at onset of end-stage renal disease was significantly higher in the positive group than in the negative group. These results help to clarify the milder clinical manifestations and molecular characteristics of male X-linked Alport syndrome patients expressing the α5(IV) chain.
X 连锁显性遗传性肾炎是由编码 IV 型胶原α5 链(α5(IV))的 COL4A5 基因突变引起的。男性患者的肾脏基底膜中完全缺乏α5(IV)被认为是一种病理特征;然而,已有超过 20%的患者发现α5(IV)染色阳性。我们回顾性研究了 52 例经基因诊断的男性 X 连锁显性遗传性肾炎患者,以评估 15 例α5(IV)阳性和 37 例α5(IV)阴性患者之间的临床特征和肾脏结局差异。α5(IV)阳性组中有 13 例患者存在非截断突变,包括 9 个错义突变、3 个框内缺失和 1 个剪接位点突变,导致转录物的小框内缺失。另外两个表现出嵌合体的体细胞突变。与α5(IV)阴性组相比,α5(IV)阳性组的错义突变更可能位于外显子 25 之前。此外,阳性组的尿蛋白水平显著较低,终末期肾病的发病年龄显著较高。这些结果有助于阐明表达α5(IV)链的男性 X 连锁显性遗传性肾炎患者更轻微的临床表现和分子特征。