Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA.
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Kidney Int. 2019 Oct;96(4):883-889. doi: 10.1016/j.kint.2019.06.016. Epub 2019 Jul 10.
Steroid-resistant nephrotic syndrome is a frequent cause of chronic kidney disease almost inevitably progressing to end-stage renal disease. More than 58 monogenic causes of SRNS have been discovered and majority of known steroid-resistant nephrotic syndrome causing genes are predominantly expressed in glomerular podocytes, placing them at the center of disease pathogenesis. Herein, we describe two unrelated families with steroid-resistant nephrotic syndrome with homozygous mutations in the KIRREL1 gene. One mutation showed high frequency in the European population (minor allele frequency 0.0011) and this patient achieved complete remission following treatment, but later progressed to chronic kidney disease. We found that mutant KIRREL1 proteins failed to localize to the podocyte cell membrane, indicating defective trafficking and impaired podocytes function. Thus, the KIRREL1 gene product has an important role in modulating the integrity of the slit diaphragm and maintaining glomerular filtration function.
激素抵抗型肾病综合征是慢性肾脏病的常见病因，几乎不可避免地会进展为终末期肾病。现已发现超过 58 种单基因导致激素抵抗型肾病综合征的原因，且大多数已知的导致激素抵抗型肾病综合征的基因主要在肾小球足细胞中表达，这使它们处于疾病发病机制的中心。在此，我们描述了两个具有激素抵抗型肾病综合征的无关家族，其 KIRREL1 基因存在纯合突变。一个突变在欧洲人群中具有较高的频率（次要等位基因频率为 0.0011），该患者经治疗后完全缓解，但后来进展为慢性肾脏病。我们发现突变型 KIRREL1 蛋白无法定位于足细胞的细胞膜，表明其转运功能缺陷，从而损害了足细胞的功能。因此，KIRREL1 基因产物在调节裂孔隔膜的完整性和维持肾小球滤过功能方面具有重要作用。
