The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2)

Abstract

Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. 25Mg2+ uptake assays demonstrated loss‐of‐function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44–0.72 mmol/L), which could not be fully corrected by Mg2+ supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR.

Crystal structure of an archaeal CorB magnesium transporter

“…7d ). Nine missense mutations in HsCNNM2 are responsible for hypomagnesemia 3 , 5 , 39 , 40 . T568I in the CBS-pair domain prevents ATP binding and Mg 2+ transport 27 , 35 .…”

Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia

“…And all four patients showed hypomagnesemia with a renal defect in Mg 2+ reabsorption. The other two homozygous variants (c.364G>A, p.Glu122Lys; c.1642G>A, p.Val548Met) (Arjona et al, 2014 ; Accogli et al, 2019 ) and 13 heterozygous in CNNM2 occurred in unrelated families (Kosmicki et al, 2017 ; Snoeijen-Schouwenaars et al, 2019 ; Bamhraz et al, 2020 ; Franken et al, 2021 ). In 24 cases, different variant domains were listed in Figure 1E .…”

Genetic and drug-induced hypomagnesemia: different cause, same mechanism

“…Mutations in the cyclin M2 gene CNNM2 cause hypomagnesemia, seizures, intellectual disability and obesity (78)(79)(80)(81) . Therefore, CNNM2 likely plays a role in brain development and metabolism as well as Mg 2+ balance (79,81) .…”

“…Mutations in the cyclin M2 gene CNNM2 cause hypomagnesemia, seizures, intellectual disability and obesity (78)(79)(80)(81) . Therefore, CNNM2 likely plays a role in brain development and metabolism as well as Mg 2+ balance (79,81) . There is a debate on whether CNNM2 and its family members CNNM1, CNNM3 and CNNM4 are the putative Na + /Mg 2+ -exchangers responsible for Mg 2 + extrusion (82,83) .…”