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Phenotypic and Genetic Heterogeneity Linked to the Magnesium Transport Mediator CNNM2

Reham Khalaf-Nazzal1*, Paula Giménez-Mascarell2, Imad M. Dweikat3, 4, Iker Oyenarte2, Dominik Müller5, Félix Claverie-Martín6 and Luis Alfonso Martínez-Cruz2
  • 1 Faculty of Medicine and Health Sciences, An-Najah National University, Physiology, Pharmacology, and Toxicology Department, Palestine
  • 2 Center for Cooperative Research in Biosciences (CIC bioGUNE), Structural Biology Unit, Spain
  • 3 Faculty of Medicine and Health Sciences, An-Najah National University, Palestine
  • 4 An-Najah National University Hospital, Pediatrics Department, Palestine
  • 5 Charité Universitäts medizin, Department of Pediatric Nephrology, Germany
  • 6 Nuestra Señora de Candelaria University Hospital, Research Unit, Spain

Metal cation transport mediator (CNNM) gene family comprises 4 isoforms (CNNM1-4) that are expressed in all human tissues except for CNNM1, which is mainly expressed in the brain. Structurally, CNNMs are complex proteins that contain an extracellular N-terminal domain preceding a DUF21 transmembrane domain, a ‘Bateman module’ and a C-terminal cNMP-binding domain (de Baaij et al., 2012). Recent studies suggest CNNM2 (cyclin M2) to be part of the long sought basolateral Mg2+ extruder at the renal distal convoluted tubule, or its regulator. The Bateman module of CNNM2, consisting of two consecutive CBS (cystathionine β-synthase) domains, associates itself in disc-like dimers commonly referred to as “CBS modules”. Interestingly, nucleotide binding triggers a conformational change in the CBS module from a twisted towards a flat disc-like structure that mostly affects the structural elements connecting the Bateman module with the transmembrane region (Corral-Rodríguez et al., 2014). Mutations in CNNM2 cause familial dominant hypomagnesaemia (Stuiver et al., 2011), a human disorder characterized by renal Mg2+ wasting that may lead to symptoms of Mg2+ depletion such as tetany, seizures and cardiac arrhythmias . On the other hand, mutations in CNNM4, the closest homologue of CNNM2, have clinical consequences that are limited to retinal function and biomineralization, and are considered the cause of autosomal-recessive cone-rod dystrophy with amelogenesis imperfecta (Parry et al., 2009; Polok et al., 2009). Recently, growing evidence highlights the role of CNNM2 in neurodevelopment. Mutations in CNNM2 have been implicated in the development of a range of neurodevelopmental phenotypes, including epilepsy, intellectual disability, schizophrenia and others (Arjona et al., 2014; Ohi, 2015). In the present study, we aim to elucidate the function of CNNM2 in the developing brain. Thus, we present the genetic origin of symptoms in two family cohorts. In the first family, three siblings of a highly consanguineous Palestinian family in which parents are first cousins, and consanguineous marriages ran over the past four generations, presented varying degree of intellectual disability, visual impairment due to cone-rode dystrophy, and Autism Spectrum Disorder. Whole exome sequencing and subsequent segregation analysis revealed the presence of homozygous pathogenic mutation in the CNNM2 gene, the parents were heterozygous carriers for that gene mutation. Magnesium blood levels were normal in the three children and their parents in several measurements. They had no symptoms of hypomagnesemia. The CNNM2 mutation in this family was found to locate in the CBS1 domain of the CNNM2 protein. The crystal structure of the mutated CNNM2 protein was not significantly different from the wild type protein, and the binding of AMP or MgATP was not dramatically affected. This suggests that the CBS1 domain could be involved in pure neurodevelopmental functions independent of its magnesium-handling role, and this mutation could have affected a protein partner binding or other functions in this protein. In the second family, another autosomal dominant CNNM2 mutation was found to run in a large family with multiple affected individuals over three generations. All affected family members had hypomagnesemia and hypermagnesuria. Oral supplementation of magnesium did not increase the levels of magnesium in serum significantly. Some affected members in this family have defects in fine motor skills such as dyslexia and dyslalia. The detected mutation is located in the N-terminal part which contains a signal peptide which is thought to be involved in sorting and routing of the protein. In this project, we describe heterogenous clinical phenotypes related to CNNM2 gene mutations and protein functions. In the first family, we report for the first time the involvement of CNNM2 in retinal phototreceptor development and function. CNNM4 is already described to be involved in retinal development. We also report for the first time the presence of a neurophenotype independent of magnesium status related to the CNNM2 protein mutation. Taking into account the different modes of inheritance and the different positions of the mutations within CNNM2 and its different structural and functional domains, it is likely that CNNM2 might be involved in a wide spectrum of psychiatric and neurological comorbidities with considerable varying phenotypes.

References

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de Baaij, J.H.F., Stuiver, M., Meij, I.C., Lainez, S., Kopplin, K., Venselaar, H., Müller, D., Bindels, R.J.M., and Hoenderop, J.G.J. (2012). Membrane topology and intracellular processing of cyclin M2 (CNNM2). J. Biol. Chem. 287, 13644–13655.

Corral-Rodríguez, M.Á., Stuiver, M., Abascal-Palacios, G., Diercks, T., Oyenarte, I., Ereño-Orbea, J., de Opakua, A.I., Blanco, F.J., Encinar, J.A., Spiwok, V., et al. (2014). Nucleotide binding triggers a conformational change of the CBS module of the magnesium transporter CNNM2 from a twisted towards a flat structure. Biochem. J. 464, 23–34.

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Ohi, K. (2015). Influences of schizophrenia risk variant rs7914558 at CNNM2 on brain structure. Br. J. Psychiatry J. Ment. Sci. 206, 343–344.

Parry, D.A., Mighell, A.J., El-Sayed, W., Shore, R.C., Jalili, I.K., Dollfus, H., Bloch-Zupan, A., Carlos, R., Carr, I.M., Downey, L.M., et al. (2009). Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am. J. Hum. Genet. 84, 266–273.

Polok, B., Escher, P., Ambresin, A., Chouery, E., Bolay, S., Meunier, I., Nan, F., Hamel, C., Munier, F.L., Thilo, B., et al. (2009). Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta. Am. J. Hum. Genet. 84, 259–265.

Stuiver, M., Lainez, S., Will, C., Terryn, S., Günzel, D., Debaix, H., Sommer, K., Kopplin, K., Thumfart, J., Kampik, N.B., et al. (2011). CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia. Am. J. Hum. Genet. 88, 333–343.

Keywords: Magnesium transport mediator, neurodevelopment, CBS1 domain, Inheritance Patterns, cone-rod dystrophy

Conference: 2nd International Conference on Educational Neuroscience, Abu Dhabi, United Arab Emirates, 5 Mar - 6 Mar, 2017.

Presentation Type: Poster Presentation

Topic: Educational Neuroscience

Citation: Khalaf-Nazzal R, Giménez-Mascarell P, Dweikat IM, Oyenarte I, Müller D, Claverie-Martín F and Martínez-Cruz L (2017). Phenotypic and Genetic Heterogeneity Linked to the Magnesium Transport Mediator CNNM2. Conference Abstract: 2nd International Conference on Educational Neuroscience. doi: 10.3389/conf.fnhum.2017.222.00035

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Received: 30 Jan 2017; Published Online: 11 Dec 2017.

* Correspondence: Dr. Reham Khalaf-Nazzal, Faculty of Medicine and Health Sciences, An-Najah National University, Physiology, Pharmacology, and Toxicology Department, Nablus, 007, Palestine, reham.khalaf@icloud.com