Four novel mutations identified in the COL4A3, COL4A4 and COL4A5 genes in 10 families with Alport syndrome.

IF 2.1 4区 医学 Q3 GENETICS & HEREDITY
Duocai Wang, Meize Pan, Hang Li, Minchun Li, Ping Li, Fu Xiong, Hongbo Xiao
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引用次数: 0

Abstract

Background: Alport syndrome (AS) is an inherited nephropathy caused by mutations in the type IV collagen genes. It is clinically characterized by damage to the eyes, ears and kidneys. Diagnosis of AS is hampered by its atypical clinical picture, particularly when the typical features, include persistent hematuria and microscopic changes in the glomerular basement membrane (GBM), are the only clinical manifestations in the patient.

Methods: We screened 10 families with suspected AS using whole exome sequencing (WES) and analyzed the harmfulness, conservation, and protein structure changes of mutated genes. In further, we performed in vitro functional analysis of two missense mutations in the COL4A5 gene (c.2359G > C, p.G787R and c.2605G > A, p.G869R).

Results: We identified 11 pathogenic variants in the type IV collagen genes (COL4A3, COL4A4 and COL4A5). These pathogenic variants include eight missense mutations, two nonsense mutations and one frameshift mutation. Notably, Family 2 had digenic mutations in the COL4A3 (p.G1170A) and UMOD genes (p.M229K). Family 3 had a digenic missense mutation (p.G997E) in COL4A3 and a frameshift mutation (p.P502L fs*151) in COL4A4. To our knowledge, four of the 11 mutations are novel mutations. In addition, we found that COL4A5 mutation relation mRNA levels were significantly decreased in HEK 293 T cell compared to control, while the cellular localization remained the same.

Conclusions: Our research expands the spectrum of COL4A3-5 pathogenic variants, which is helpful for clinical and scientific research.

在 10 个阿尔波特综合征家族中发现 COL4A3、COL4A4 和 COL4A5 基因的四个新突变。
背景:阿尔波特综合征(AS)是一种遗传性肾病,由 IV 型胶原蛋白基因突变引起。其临床特征是眼睛、耳朵和肾脏受损。AS的诊断因其不典型的临床表现而受到阻碍,尤其是当典型特征(包括持续性血尿和肾小球基底膜(GBM)的微小变化)是患者唯一的临床表现时:方法:我们使用全外显子组测序(WES)筛选了10个疑似强直性脊柱炎家族,分析了突变基因的有害性、保守性和蛋白结构变化。此外,我们还对 COL4A5 基因中的两个错义突变(c.2359G > C, p.G787R 和 c.2605G > A, p.G869R)进行了体外功能分析:结果:我们在 IV 型胶原蛋白基因(COL4A3、COL4A4 和 COL4A5)中发现了 11 个致病变异。这些致病变异包括 8 个错义突变、2 个无义突变和 1 个框移突变。值得注意的是,家族 2 的 COL4A3 基因(p.G1170A)和 UMOD 基因(p.M229K)发生了二基因突变。家族 3 的 COL4A3 基因有一个二基因错义突变(p.G997E),COL4A4 基因有一个移帧突变(p.P502L fs*151)。据我们所知,这 11 个突变中有 4 个是新型突变。此外,我们还发现,与对照组相比,COL4A5突变相关的mRNA水平在HEK 293 T细胞中显著下降,而细胞定位则保持不变:我们的研究扩大了 COL4A3-5 致病变异的范围,有助于临床和科学研究。
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来源期刊
BMC Medical Genomics
BMC Medical Genomics 医学-遗传学
CiteScore
3.90
自引率
0.00%
发文量
243
审稿时长
3.5 months
期刊介绍: BMC Medical Genomics is an open access journal publishing original peer-reviewed research articles in all aspects of functional genomics, genome structure, genome-scale population genetics, epigenomics, proteomics, systems analysis, and pharmacogenomics in relation to human health and disease.
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