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Abstract: PO2001

Functional Analysis of Novel CNNM2 Mutation in Autosomal Dominant Hypomagnesemia with Seizure

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Author

  • Tseng, Min-hua, Chang Gung Medical Foundation, Taoyuan, Taiwan
Background

CNNM2 has been identified to be the responsible gene for patients with hypomagnesemia, seizure, intellectual disability (HSMR) syndrome. The functional impact of mutations in CNNM2 remains unknown.

Methods

We have identified 1-year-old infant with HSMR featuring severe hypomagnesemia with renal magnesium (Mg++) wasting requiring higher dose of Mg++ supplementation. Whole exome sequencing (WES) with direct Sanger sequence was performed to identify the responsible gene. The functional assay of this identified mutants was examined in vitro studies.

Results

With WES, we identified a de novo heterozygous mutation c.G1439T (R480L) in CBS domain of CNNM2 gene without any other gene mutations related to hypomagnesemia. This missense CNNM2 P480L mutation was conserved in different species and very pathogenic based on the different software prediction models. This R480L mutation impaired the interaction between CNNM2 and ATP-Mg2+ by simulation model. In vitro studies, This CNNM2-R480L protein expression was higher than CNNM2-wild type. Immunocytochemistry images demonstrated the proper localization of CNNM2-R480L and CNNM2-wild type. Mg2+ efflux assay revealed significant increase of intracellular Mg2+ Green in CNNM2-R480L than CNNM2-WT, indicative of CNNM2-R480L mutation blocking Mg2+ efflux.

Conclusion

This novel R480L mutation in CBS domain of CNNM2 gene diminishes the Mg2+ efflux probably through the impaired binding between Mg2+-ATP and CNNM2, accounting for refractory hypomagnesemia.

Funding

  • Government Support – Non-U.S.