Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure

Abstract

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.

Rare cause of recurrent hypocalcaemia and functional hypoparathyroidism due to hypomagnesaemia caused byTRPM6gene mutation

“…The kidney and the intestinal tract are the principal organs involved in Mg homeostasis. Mutations affecting the intestinal and renal transport of Mg 2+ ions like transient receptor potential cation ( TRPM6 ), pterin-4-alpha carbinolamine dehydratase 1 ( PCBD1 ) or cystathionine-β-synthase-pair domain divalent metal cation transport mediator 2 ( CNNM2 ) gene can lead to HSH 4–6. Hypomagnesaemia causes hypocalcaemia by three mechanisms: end-organ unresponsiveness to PTH, impaired release of PTH and impaired formation of 1,25-dihydroxy vitamin D 2.…”

An Update on Hypomagnesemia and Hypermagnesemia

“…In the last decade, transgenic murine models and the identification of their disorders have provided valuable insights into the molecular mechanisms of renal magnesium absorption [5]. The spectrum of etiologies of hereditary magnesium wasting related to monogenic mutations yielding dysfunctional transporter proteins, is still expanding [1,4,46]. Phenotypic traits alluding to a genetic etiology and warranting advice from the geneticist apart from family history, are features like early-onset hypomagnesemia, dysmorphic characteristics, neurosensorial hearing loss, cognitive dysfunction, epilepsy, diabetes, nephrocalcinosis and biochemical features such as hypercalciuria, metabolic alkalosis, and hypokalemia.…”

“…Also, the list of etiologies of magnesium deficiency is still expanding. Novel hereditary causes of hypomagnesemia are being deciphered in tight conjunction with the exploration of the various pathways of renal tubular magnesium transport [4,5]. The causal role of commonly used drugs such as proton pump inhibitors or, more rarely, cetuximab (monoclonal antibodies against epidermal growth factor receptor) adds to the increasing list of drugs associated with decreased magnesium absorption or enhanced urinary loss.…”

CNNM2 genetic variant induced hereditary renal hypomagnesemia: A case report

“…The hereditary renal hypomagnesemia is a rare disease that caused by genetic variant-induced dysfunction of magnesium reabsorption in the kidney [1]. Magnesium is one of the most crucial cations in the human body, constituting a variety of enzymes that are involved in DNA synthesis, protein interaction and oxidative phosphorylation [2]. In addition, study has shown that magnesium possesses inhibitory effect on excitability of central nervous system, skeletal muscle and cardiomyocytes [3].…”