Bindels, René J.m.

Dahan, Karin

de Baaij, Jeroen H.F.

Devuyst, Olivier

Dorresteijn, Eiske M.

Hennekam, Eric A.M.

Hoenderop, Joost G.j.

Kamsteeg, Erik-Jan

Knoers, Nine V.A.M.

Meijer, Rowdy

Muller, Michelle

van den Dorpel, Marinus A.

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GENETIC DISEASES ANDMOLECULARGENETICSSP019 RECURRENT FXYD2 P.GLY41ARGMUTATION IN PATIENTSWITH ISOLATED DOMINANT HYPOMAGNESEMIAJeroen H.F. de Baaij1, Eiske M. Dorresteijn2, Eric A.M. Hennekam3,Erik-Jan Kamsteeg4, Rowdy Meijer4, Karin Dahan5, Michelle Muller6, MarinusA. van den Dorpel7, René J.m. Bindels8, Joost G.j. Hoenderop8, Olivier Devuyst9and Nine V.A.M. Knoers31Radboud University Medical Centre, Physiology, Nijmegen, The Netherlands,2Erasmus MC, Sophia Childrens Hospital, Pediatric Nephrology, Rotterdam, TheNetherlands, 3University Medical Centre Utrecht, Medical Genetics, Utrecht, TheNetherlands, 4Radboud University Medical Center, Human Genetics, Nijmegen,The Netherlands, 5Université Catholique de Louvain, Institut de Génétique et dePathologie, Louvain, Belgium, 6Centre Hospitalier Peltzer-La Tourelle, Nephrologie,Verviers, Belgium, 7Maasstad Hospital, Internal Medicine, Rotterdam, TheNetherlands, 8Radboud University Medical Center, Physiology, Nijmegen, TheNetherlands, 9University of Zürich, Institute of Physiology,Zürich, SwitzerlandIntroduction and Aims:Magnesium (Mg2+) is an essential mineral for cell growth,neuroplasticity and muscle contraction. Blood Mg2+ levels below 0.7 mmol/L maycause a heterogeneous clinical phenotype, including muscle cramps, epilepsy anddisturbances in K+ and Ca2+ homeostasis. Over the last decade, the genetic origin ofseveral familial forms of hypomagnesemia has been delineated. In 2000, mutations inFXYD2, encoding the γ-subunit of the Na+-K+-ATPase, were identified to causeisolated dominant hypomagnesemia (IDH) in a large Dutch family suffering fromhypomagnesemia, hypocalciuria and chondrocalcinosis. However, additional patientswere never identified.Methods: Here, two families with hypomagnesemia and hypocalciuria were screenedfor mutations in the FXYD2 gene. Moreover, the patients were clinically andgenetically characterized.Results:We report a p.Gly41Arg FXYD2 mutation in two families withhypomagnesemia and hypocalciuria. The patients suffered from muscle cramps,chondrocalcinosis and epilepsy. The p.Gly41Arg substitution introduces a chargedamino acid residue in the predicted transmembrane region of the γ-subunit of the Na+-K+-ATPase. As a consequence, the γ-subunit lacks post-translational modificationsand is not routed to the plasma membrane. Interestingly, this is exactly the samemutation as was described in the original study. Haplotype analysis revealed anoverlapping haplotype in all families, suggesting a founder effect. However, extensivegenealogical analysis did not reveal a common ancestor in 9-12 generations.Conclusions: The recurrent p.Gly41Arg FXYD2 mutation in two new families withisolated dominant hypomagnesemia confirms that the FXYD2 mutation causeshypomagnesemia. Until now, no other FXYD2 mutations have been reported whichcould indicate that other FXYD2 mutations will not cause hypomagnesemia or areembryonically lethal.© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.Nephrology Dialysis Transplantation 30 (Supplement 3): iii381–iii392, 2015doi:10.1093/ndt/gfv187.19

SP019RECURRENT FXYD2 P.GLY41ARG MUTATION IN PATIENTS WITH ISOLATED DOMINANT HYPOMAGNESEMIA

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SP019RECURRENT FXYD2 P.GLY41ARG MUTATION IN PATIENTS WITH ISOLATED DOMINANT HYPOMAGNESEMIA

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