Kidney Week

Abstract: PO1360

Cyclin M2 (CNNM2) Is Essential for Development and Systemic Magnesium Homeostasis

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Franken, Gijs A.C., Radboudumc, Nijmegen, Gelderland, Netherlands

Gijs A.C. Franken

• Seker, Murat, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Murat Seker,

• Latta, Femke, Radboudumc, Nijmegen, Gelderland, Netherlands

Femke Latta,

• Bos, Caro, Radboudumc, Nijmegen, Gelderland, Netherlands

Caro Bos,

• Hoenderop, Joost, Radboudumc, Nijmegen, Gelderland, Netherlands

Joost Hoenderop,

• Bindels, René J., Radboudumc, Nijmegen, Gelderland, Netherlands

René J. Bindels,

• Breiderhoff, Tilman, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Tilman Breiderhoff,

• Schlingmann, Karl P., Universitatsklinikum Munster, Munster, Nordrhein-Westfalen, Germany

Karl P. Schlingmann,

• Müller, Dominik, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Dominik Müller,

• De Baaij, Jeroen H.F., Radboudumc, Nijmegen, Gelderland, Netherlands

Jeroen H.F. De Baaij,

Background

Patients with mutations in the Cyclin M2 (CNNM2) gene display hypomagnesaemia and intellectual disability. CNNM2 is highly expressed in the distal convoluted tubule, where it is involved in renal magnesium (Mg²⁺) reabsorption. However, the complete phenotypical spectrum of the CNNM2-related disorder remains unknown. We characterised a large patient cohort with novel CNNM2 variants and used transgenic mouse models to investigate the role of CNNM2 in Mg²⁺ homeostasis.

Methods

The identified CNNM2 variants were found in a cohort of hypomagnesaemic patients and characterised using ²⁵Mg²⁺transport assays in HEK293 cells. In addition, Cnnm2 deficient mice were developed using CRISPR/Cas9 technology and exposed to deficient or saturated Mg²⁺ diets for two weeks. Using metabolic cages, the 24-hour urinary and faecal excretion for Mg²⁺ was determined.

Results

Eleven patients were identified with novel dominant variants in CNNM2. Using ²⁵Mg²⁺ transport assays in HEK293 cells, seven variants showed decreased ²⁵Mg²⁺ transport compared to wild type. These pathogenic mutations resulted in decreased membrane expression of CNNM2. The phenotype of these patients was compared with those previously published. Patients with pathogenic CNNM2 mutations had a mean plasma Mg²⁺ level of 0.54 ± 0.08 mmol/L. Neurological manifestations, such as seizures (79%), intellectual disability (92%) and speech difficulties (91%) were prevalent. Interestingly, obesity was often (80%) found. To elucidate the physiological function of CNNM2, we generated knockout mouse models. Approximately 30% of Cnnm2^-/- embryos displayed exencephaly and all died shortly after birth. Both Cnnm2^-/-, Cnnm2^+/- and Cnnm2^+/- pups, and Cnnm2^+/- adult mice showed decreased serum Mg²⁺ levels and increased Ca²⁺ levels, independent when fed with deficient or saturated Mg²⁺ diets. At basal level, adult Cnnm2^+/- mice showed increased faecal Mg²⁺ and Ca²⁺ excretion compared to control.

Conclusion

CNNM2 is important for normal development and Mg²⁺ homeostasis, although the link remains elusive. Our mouse study suggests a putative role of CNNM2 in the intestine, which could have implications for the treatment of patients suffering from CNNM2 mutations.