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- Publisher Website: 10.3389/fimmu.2022.962986
- Scopus: eid_2-s2.0-85138666158
- PMID: 36159820
- WOS: WOS:000859579600001
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Article: Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis
Title | Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis |
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Authors | |
Keywords | kidney transplantation MDH2 next-generation RNA sequencing recurrent focal segmental glomerulosclerosis whole genome sequencing |
Issue Date | 2022 |
Citation | Frontiers in Immunology, 2022, v. 13, article no. 962986 How to Cite? |
Abstract | Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx. To confirm the functional role of the identified gene with the MDH2 c.26C >T mutation, a homozygous MDH2 c.26C >T mutation in HMy2.CIR cell line was induced by CRISPR/Cas9 and co-cultured with podocytes, mesangial cells, or HK2 cells, respectively, to detect the potential pathogenicity of the c.26C >T variant in MDH2. A total of 32 nonsynonymous single nucleotide polymorphisms (SNPs) and 610 differentially expressed genes (DEGs) related to rFSGS were identified. DEGs are mainly enriched in the immune and metabolomic-related pathways. A variant in MDH2, c.26C >T, was found in all patients with rFSGS, which was also accompanied by lower levels of mRNA expression in PBMCs from relapsed patients compared with patients with remission after KTx. Functionally, co-cultures of HMy2.CIR cells overexpressing the mutant MDH2 significantly inhibited the expression of synaptopodin, podocin, and F-actin by podocytes compared with those co-cultured with WT HMy2.CIR cells or podocytes alone. We identified that MDH2 is a novel rFSGS susceptibility gene in patients with recurrence of FSGS after KTx. Mutation of the MDH2 c.26C >T variant may contribute to progressive podocyte injury in rFSGS patients. |
Persistent Identifier | http://hdl.handle.net/10722/324516 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Shen, Qixia | - |
dc.contributor.author | Teng, Lisha | - |
dc.contributor.author | Wang, Yucheng | - |
dc.contributor.author | Guo, Luying | - |
dc.contributor.author | Xu, Feng | - |
dc.contributor.author | Huang, Hongfeng | - |
dc.contributor.author | Xie, Wenqing | - |
dc.contributor.author | Zhou, Qin | - |
dc.contributor.author | Chen, Ying | - |
dc.contributor.author | Wang, Junwen | - |
dc.contributor.author | Mao, Youying | - |
dc.contributor.author | Chen, Jianghua | - |
dc.contributor.author | Jiang, Hong | - |
dc.date.accessioned | 2023-02-03T07:03:42Z | - |
dc.date.available | 2023-02-03T07:03:42Z | - |
dc.date.issued | 2022 | - |
dc.identifier.citation | Frontiers in Immunology, 2022, v. 13, article no. 962986 | - |
dc.identifier.uri | http://hdl.handle.net/10722/324516 | - |
dc.description.abstract | Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx. To confirm the functional role of the identified gene with the MDH2 c.26C >T mutation, a homozygous MDH2 c.26C >T mutation in HMy2.CIR cell line was induced by CRISPR/Cas9 and co-cultured with podocytes, mesangial cells, or HK2 cells, respectively, to detect the potential pathogenicity of the c.26C >T variant in MDH2. A total of 32 nonsynonymous single nucleotide polymorphisms (SNPs) and 610 differentially expressed genes (DEGs) related to rFSGS were identified. DEGs are mainly enriched in the immune and metabolomic-related pathways. A variant in MDH2, c.26C >T, was found in all patients with rFSGS, which was also accompanied by lower levels of mRNA expression in PBMCs from relapsed patients compared with patients with remission after KTx. Functionally, co-cultures of HMy2.CIR cells overexpressing the mutant MDH2 significantly inhibited the expression of synaptopodin, podocin, and F-actin by podocytes compared with those co-cultured with WT HMy2.CIR cells or podocytes alone. We identified that MDH2 is a novel rFSGS susceptibility gene in patients with recurrence of FSGS after KTx. Mutation of the MDH2 c.26C >T variant may contribute to progressive podocyte injury in rFSGS patients. | - |
dc.language | eng | - |
dc.relation.ispartof | Frontiers in Immunology | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | kidney transplantation | - |
dc.subject | MDH2 | - |
dc.subject | next-generation RNA sequencing | - |
dc.subject | recurrent focal segmental glomerulosclerosis | - |
dc.subject | whole genome sequencing | - |
dc.title | Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis | - |
dc.type | Article | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.3389/fimmu.2022.962986 | - |
dc.identifier.pmid | 36159820 | - |
dc.identifier.pmcid | PMC9495259 | - |
dc.identifier.scopus | eid_2-s2.0-85138666158 | - |
dc.identifier.volume | 13 | - |
dc.identifier.spage | article no. 962986 | - |
dc.identifier.epage | article no. 962986 | - |
dc.identifier.eissn | 1664-3224 | - |
dc.identifier.isi | WOS:000859579600001 | - |