Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure
CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. Mutations in CNNM2 have been reported to cause hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome. However, the clinical and functional effect of CNNM2 mutations remains incompletely underst...
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| Format: | Article |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.875013/full |
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| author | Min-Hua Tseng Min-Hua Tseng Sung-Sen Yang Chih-Chien Sung Jhao-Jhuang Ding Yu-Juei Hsu Shih-Ming Chu Shih-Hua Lin |
| author_facet | Min-Hua Tseng Min-Hua Tseng Sung-Sen Yang Chih-Chien Sung Jhao-Jhuang Ding Yu-Juei Hsu Shih-Ming Chu Shih-Hua Lin |
| author_sort | Min-Hua Tseng |
| collection | DOAJ |
| description | CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. Mutations in CNNM2 have been reported to cause hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome. However, the clinical and functional effect of CNNM2 mutations remains incompletely understood. We report our clinical encounter with a 1-year-old infant with HSMR features. Mutation screening for this trio family was performed using next-generation sequencing (NGS)-based whole exome sequencing (WES) with the identified mutation verified by Sanger sequencing. We identified a de novo heterozygous mutation c.G1439T (R480L) in the essential cystathionine β-synthase (CBS) domain of CNNM2 encoding CNNM2 (cyclin M2) without any other gene mutations related to hypomagnesemia. The amino acid involved in this missense mutation was conserved in different species. It was also found to be pathogenic based on the different software prediction models and ACGME criteria. In vitro studies revealed a higher expression of the CNNM2-R480L mutant protein compared to that of the wild-type CNNM2. Like the CNNM2-wild type, proper localization of CNNM2-R480L was shown on immunocytochemistry images. The Mg2+ efflux assay in murine DCT (mDCT) cells revealed a significant increase in intracellular Mg2+ green in CNNM2-R480L compared to that in CNNM2-WT. By using a simulation model, we illustrate that the R480L mutation impaired the interaction between CNNM2 and ATP-Mg2+. We propose that this novel R480L mutation in the CNNM2 gene led to impaired binding between Mg2+-ATP and CNNM2 and diminished Mg2+ efflux, manifesting clinically as refractory hypomagnesemia. |
| first_indexed | 2024-12-12T17:11:04Z |
| format | Article |
| id | doaj.art-db87c7a1664f4b069d816ad75e7ddf94 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-12T17:11:04Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-db87c7a1664f4b069d816ad75e7ddf942022-12-22T00:17:53ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-06-011310.3389/fgene.2022.875013875013Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With SeizureMin-Hua Tseng0Min-Hua Tseng1Sung-Sen Yang2Chih-Chien Sung3Jhao-Jhuang Ding4Yu-Juei Hsu5Shih-Ming Chu6Shih-Hua Lin7Division of Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, TaiwanDepartment of Pediatrics, Xiamen Chang Gung Hospital, Ximen, ChinaDivision of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDivision of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDepartment of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDivision of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanDivision of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, TaiwanDivision of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanCNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. Mutations in CNNM2 have been reported to cause hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome. However, the clinical and functional effect of CNNM2 mutations remains incompletely understood. We report our clinical encounter with a 1-year-old infant with HSMR features. Mutation screening for this trio family was performed using next-generation sequencing (NGS)-based whole exome sequencing (WES) with the identified mutation verified by Sanger sequencing. We identified a de novo heterozygous mutation c.G1439T (R480L) in the essential cystathionine β-synthase (CBS) domain of CNNM2 encoding CNNM2 (cyclin M2) without any other gene mutations related to hypomagnesemia. The amino acid involved in this missense mutation was conserved in different species. It was also found to be pathogenic based on the different software prediction models and ACGME criteria. In vitro studies revealed a higher expression of the CNNM2-R480L mutant protein compared to that of the wild-type CNNM2. Like the CNNM2-wild type, proper localization of CNNM2-R480L was shown on immunocytochemistry images. The Mg2+ efflux assay in murine DCT (mDCT) cells revealed a significant increase in intracellular Mg2+ green in CNNM2-R480L compared to that in CNNM2-WT. By using a simulation model, we illustrate that the R480L mutation impaired the interaction between CNNM2 and ATP-Mg2+. We propose that this novel R480L mutation in the CNNM2 gene led to impaired binding between Mg2+-ATP and CNNM2 and diminished Mg2+ efflux, manifesting clinically as refractory hypomagnesemia.https://www.frontiersin.org/articles/10.3389/fgene.2022.875013/fullCNNM2hypomagnesemiaseizureHSMR syndromerenal magnesium wasting |
| spellingShingle | Min-Hua Tseng Min-Hua Tseng Sung-Sen Yang Chih-Chien Sung Jhao-Jhuang Ding Yu-Juei Hsu Shih-Ming Chu Shih-Hua Lin Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure Frontiers in Genetics CNNM2 hypomagnesemia seizure HSMR syndrome renal magnesium wasting |
| title | Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure |
| title_full | Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure |
| title_fullStr | Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure |
| title_full_unstemmed | Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure |
| title_short | Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure |
| title_sort | novel cnnm2 mutation responsible for autosomal dominant hypomagnesemia with seizure |
| topic | CNNM2 hypomagnesemia seizure HSMR syndrome renal magnesium wasting |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.875013/full |
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