A multidisciplinary team composed of researchers from Radboudumc and Radboud University Nijmegen (The Netherlands), University of Vienna (Austria), University Children's Hospital (Münster, Germany) and Universities of Münster and Oldenburg (Germany), has established the genetic etiology of disease in patients with a complex symptomatology consisting of mental retardation, seizures, locomotor impairments and hypomagnesemia. These findings are published in the journal PLoS Genetics.
In this study, a cohort of patients with hypomagnesemia of unknown genetic origin was examined. Targeted sequencing revealed the presence of inherited and de novomutations in the gene Cyclin M2 (CNNM2) in a distinct group of these patients which in addition to hypomagnesemia, suffered from mental retardation, seizures and locomotor disability. Furthermore, magnetic resonance imaging showed that patients with homozygous CNNM2 mutations have brain malformations. By combining in vitroand in vivostudies, the causal link between CNNM2 and disease was established and the pathomechanism of disease revealed. The deleteriousness of CNNM2 mutations for renal Mg2+ reabsorption was illustrated by decreased Mg2+ uptake in mammalian cells overexpressing mutant CNNM2 proteins and increased Mg2+ wasting in zebrafish with dysfunctional CNNM2. The zebrafish model of CNNM2 dysfunction also showed aberrant brain development and neurological abnormalities, features that were congruent with the mental retardation, seizures and locomotor disabilities diagnosed in patients. Remarkably, the functional equivalence between zebrafish and human CNNM2 was demonstrated in rescue experiments where the pathological features displayed by the zebrafish model with dysfunctional CNNM2 were abrogated by overexpression of the mammalian CNNM2 gene. Together, these findings showed that CNNM2 is key to normal brain development, renal Mg2+ reabsorption and neurological functioning being its dysfunction causative of mental retardation, seizures and locomotor disability in human patients with hypomagnesemia. By providing a cellular (in vitro) and a zebrafish (in vivo) model of the disease, the testing of different therapeutical procedures to ameliorate the symptoms of CNNM2 patients is now plausible.
Publication: Arjona FJ*, de Baaij JHF*, Schlingmann KP*, Lameris ALL, van Wijk E, Flik G, Regele S, Korenke GC, Neophytou B, Rust S, Reintjes N, Konrad M, Bindels RJ, Hoenderop JG. CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genet, 2014.
*Contributed equally to this work
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