Female X-linked Alport syndrome with somatic mosaicism
Female X-linked Alport syndrome with somatic mosaicism
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女性 X 连锁 Alport 综合征伴体细胞嵌合
DOI：
10.1007/s10157-016-1352-y
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Iijima K.
中科院分区：
文献类型：
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作者：
Yokota K;Nozu K;Minamikawa S;Yamamura T;Nakanishi K;Kaneda H;Hamada R;Nozu Y;Shono A;Ninchoji T;Morisada N;Ishimori S;Fujimura J;Horinouchi T;Kaito H;Nakanishi K;Morioka I;Taniguchi-Ikeda M;Iijima K.
X连锁Alport综合征（XLAS）是一种进行性遗传性肾病。尽管XLAS男性患者通常在30岁之前发生终末期肾病，但有些男性表现出较轻的表型，并具有IV型胶原α5基因（COL4A5）的体细胞嵌合体变体，严重程度取决于变体频率。在女性中，XLAS中很少报告体细胞镶嵌变异，并且尚不清楚是什么决定了严重程度。方法使用下一代测序检测到两名在COL4A5中具有体细胞镶嵌突变的女性，变异频率分别为17.9%和22.1%。1例仅出现血尿。然而，另一个有中度蛋白尿，这是她这个年龄的女性XLAS患者的严重表型。严重的表型的分子机制进行了研究，通过检查尿沉渣细胞和X染色体失活模式的变异频率，并通过寻找修改器的足细胞相关基因的变异使用下一代sequencing.ResultsThe严重的表型患者的变异频率为36.6%的尿沉渣细胞，这是不显着高，她也没有表现出歪斜的X染色体失活。然而，她没有杂合子变异inCOL4A3，这可能会影响severity.ConclusionFactors确定女性XLAS患者的严重程度仍不清楚。1例COL4A5体细胞变异患者表现为严重的表型，无X染色体失活，可能来源于COL4A3和COL4A5的双基因变异。需要进一步的研究来确定导致严重表型的女性XLAS背后的分子机制。
BackgroundX-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen α5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity.MethodsTwo females with somatic mosaic mutations inCOL4A5with variant frequencies of 17.9 and 22.1% were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing.ResultsThe severe phenotype patient had a variant frequency of 36.6% in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant inCOL4A3, which can affect severity.ConclusionFactors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant inCOL4A5showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants inCOL4A3andCOL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.