Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome
Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome
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DOI：
10.1093/ndt/gfy028
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发表时间：
2019-03-01
影响因子：
6.1
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
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作者：
Braun, Daniela A.;Warejko, Jillian K.;Hildebrandt, Friedhelm
肾病综合征（NS）是一种慢性肾脏疾病，其特征是尿蛋白大量丢失，引起低白蛋白血症和水肿。一般来说，大约15%的儿童期发病病例对类固醇治疗无反应，被归类为类固醇耐药NS（SRNS）。在大约30%的SRNS病例中，可以在44个单基因SRNS基因中的一个中检测到致病突变。基因LAMA 5编码层粘连蛋白-5，其是肾小球基底膜的必需组分。在orthopathy基因Lama 5的一个亚型突变的小鼠发展蛋白尿和血尿。方法要确定其他单基因的原因NS，我们进行了全外显子组测序在300个家庭与小儿NS。在血缘关系的家庭，我们应用纯合性映射，以确定潜在的隐性mutation.Results基因组候选位点在三个家庭，在已知的NS基因的突变被排除在外，但在其中的一个隐性的，单基因的原因NS是强烈怀疑的基础上系谱信息，我们确定了纯合变异的意义不明（VUS）的基因LAMA 5。虽然所有受影响的个人有非综合征的NS与早期发病的疾病，他们的临床结果和免疫抑制剂治疗的反应显着different.Conclusion我们在这里确定隐性VUS的基因LAMA 5在部分治疗反应的NS患者。需要更多的数据来确定这些VUS在疾病管理中的影响。然而，疾病的家族发生、遗传图谱数据和概括NS表型的小鼠模型表明，这些遗传变异可能是导致儿科患者发生NS的遗传因素。
Background Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, approximate to 15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In approximate to 30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria.Methods To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation.Results In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably.Conclusion We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.