Novel pathogenic variants in CUBN uncouple proteinuria from renal function

作者全名："Gan, Chun; Zhou, Xindi; Chen, Dan; Chi, Huan; Qiu, Jiawen; You, Hui; Chen, Yaxi; Wang, Mo; Yang, Haiping; Jiang, Wei; Li, Qiu"

作者地址："[Gan, Chun; Zhou, Xindi; Chen, Dan; Chi, Huan; Qiu, Jiawen; You, Hui; Wang, Mo; Yang, Haiping; Jiang, Wei; Li, Qiu] Chongqing Med Univ, Pediat Res Inst,Chongqing Key Lab Pediat,Children, Dept Nephrol,China Int Sci & Technol Cooperat Bas, Minist Educ,Key Lab Child Dev & Disorders,Natl Cl, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Ctr Lipid Res, Chongqing, Peoples R China; [Chen, Yaxi] Chongqing Med Univ, Minist Educ, Key Lab Mol Biol Infect Dis, Inst Viral Hepatitis,Dept Infect Dis,Affiliated H, Chongqing, Peoples R China"

通信作者："Jiang, W; Li, Q (通讯作者)，Chongqing Med Univ, Pediat Res Inst,Chongqing Key Lab Pediat,Children, Dept Nephrol,China Int Sci & Technol Cooperat Bas, Minist Educ,Key Lab Child Dev & Disorders,Natl Cl, Chongqing, Peoples R China."

来源：JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000870755900005

JCR分区：Q1

影响因子：7.4

年份：2022

卷号：20

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Pathogenic variants; CUBN; Amnionless; Proteinuria

摘要："Background Proteinuria is an unfavorable clinical condition highly associated with a risk of renal and cardiovascular disease in chronic kidney disease (CKD). However, whether all proteinuria forms are linked to renal impairment are still unclear. Cubilin is an endocytic receptor highly expressed in renal proximal tubules mediating uptake of albumin, transferrin and alpha 1-microglobulin. Methods Exome sequencing method initially identified candidate genes. With the application of exome sequencing combined with Sanger sequencing, we further focused on CUBN through bioinformatics analysis. The pathogenic effects of the potentially causative variants were verified utilizing complementary analysis of clinical data and systematic characterization of the variants' expression and function with clinical samples and in vitro experiments in HEK293T cell lines along with in vivo experiments in mice. Results In this study, we identified four novel variants locating after the vitamin B12 (vitB12)-binding domain of Cubilin (encoded by CUBN, NM_001081.3: c.4397G > A (p.C1466Y), c.6796C > T (p.R2266X), c.6821 + 3A > G and c.5153_5154delCT (p.S1718X)) in two families. Moreover, the variants severely affected the expression and function of Cubilin in renal proximal tubules and caused albuminuria, increasing levels in urine transferrin and alpha 1-microglobulin, but without progressive glomerular filtration barrier (GFB) impairment, vitB12 deficiencies or abnormal blood levels of HDL and albumin. Further mechanistic insights showed that the variants after the vitB12-binding domain of CUBN merely disrupted the association with Amnionless (AMN) that exhibited aberrant localization in cell cytoplasm rather than membrane. Conclusions Here, our findings suggested that different mutation types after the vitB12-binding domain of CUBN uncouple proteinuria from glomerular filtration barrier, that may be an unexpectedly common benign condition in humans and may not require any proteinuria-lowering treatment or renal biopsy."

基金机构："Multi-Center Innovation Platform for Early Development and Major Diseases of Perinatal Newborns in Different Altitude Areas (Special Funds for The Central Government to Guide Local Scientific and Technological Development); Second Batch of Funds for Chongqing Talents and Famous Teachers [020210]; National Natural Science Foundation of China [81970618, 82200906]; Postgraduate Scientific Research & Innovation Program of Chongqing City [CYB21181]"

基金资助正文："This study was supported by grants from Multi-Center Innovation Platform for Early Development and Major Diseases of Perinatal Newborns in Different Altitude Areas (Special Funds for The Central Government to Guide Local Scientific and Technological Development), the Second Batch of Funds for Chongqing Talents and Famous Teachers (No. 020210), the National Natural Science Foundation of China (No. 81970618 and No. 82200906) and Postgraduate Scientific Research & Innovation Program of Chongqing City (No. CYB21181)."