CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia.
CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia.
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DOI：
10.1371/journal.pgen.1004267
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发表时间：
2014-04
期刊：
影响因子：
4.5
通讯作者：
Hoenderop JG
中科院分区：
文献类型：
--
作者：
Arjona FJ;de Baaij JH;Schlingmann KP;Lameris AL;van Wijk E;Flik G;Regele S;Korenke GC;Neophytou B;Rust S;Reintjes N;Konrad M;Bindels RJ;Hoenderop JG
智力残疾和癫痫发作通常与低镁血症有关，并具有重要的遗传成分。然而，由于相当大的遗传异质性和临床可变性，寻找智力残疾和癫痫发作的遗传起源往往仍然具有挑战性。在这项研究中，我们在五个患有智力迟钝、癫痫发作和低镁血症的家庭中发现了CNNM2的新突变。首次观察到CNNM2突变的隐性遗传模式。重要的是，隐性CNNM2突变的患者会出现脑畸形和严重的智力残疾。此外，三名中度精神残疾患者被证明携带CNNM2基因的新杂合错义突变。为了阐明CNNM2的生理作用并解释疾病的病理机制，我们结合体外活性测定和斑马鱼敲低模型系统研究了CNNM2的功能。利用稳定的Mg2+同位素，我们证明了CNNM2增加HEK293细胞对Mg2+的摄取，这一过程是通过调节Mg2+渗透性阳离子通道TRPM7发生的。相比之下，表达突变的CNNM2蛋白的细胞没有显示出Mg2+摄取增加。在斑马鱼中，cnnm2亚型的敲低导致大脑发育紊乱，包括神经发育障碍，如胚胎自发收缩增加和触摸诱发的弱逃避行为，以及体内Mg含量降低，表明肾脏Mg2+吸收受损。这些表型是通过注射哺乳动物野生型Cnnm2 cRNA来恢复的，而哺乳动物突变型Cnnm2 cRNA并没有改善斑马鱼的敲除表型。因此，我们得出结论，CNNM2是脑发育、神经功能和Mg2+稳态的基础。通过建立CNNM2遗传疾病的功能丧失斑马鱼模型，我们提供了一个独特的系统来测试靶向CNNM2的治疗药物，并监测它们对脑和肾表型的影响。智力迟钝影响1-3%的人口，有很强的遗传病因。因此，早期识别智力迟钝的遗传原因对于疾病的诊断具有重要意义，可以预测疾病的进展并确定治疗方案。在这项研究中，我们发现编码细胞周期蛋白M2 （CNNM2）的基因突变是导致低镁血症患者智力迟钝和癫痫发作的原因。特别是，在隐性遗传模式的患者中，CNNM2功能失调导致的智力残疾非常严重，并伴有严重的运动技能限制和提示早期大脑发育受损的大脑畸形。虽然低镁血症与几种神经系统疾病有关，但癫痫发作和精神残疾患者的Mg2+状态并未定期评估。我们的研究结果证实CNNM2是肾镁处理、大脑发育和神经功能的重要蛋白，从而解释了CNNM2（功能失调）突变引起的人类疾病的生理学。CNNM2突变应考虑到癫痫发作和精神残疾患者，特别是合并低镁血症的患者。
Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in CNNM2 in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of CNNM2 mutations was observed. Importantly, patients with recessive CNNM2 mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry de novo heterozygous missense mutations in the CNNM2 gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining in vitro activity assays and the zebrafish knockdown model system. Using stable Mg2+ isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells and that this process occurs through regulation of the Mg2+-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg2+ uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg2+ absorption. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg2+ homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype. Mental retardation affects 1–3% of the population and has a strong genetic etiology. Consequently, early identification of the genetic causes of mental retardation is of significant importance in the diagnosis of the disease, as predictor of the progress of the disease and for the determination of treatment. In this study, we identify mutations in the gene encoding for cyclin M2 (CNNM2) to be causative for mental retardation and seizures in patients with hypomagnesemia. Particularly, in patients with a recessive mode of inheritance, the intellectual disability caused by dysfunctional CNNM2 is dramatically severe and is accompanied by severely limited motor skills and brain malformations suggestive of impaired early brain development. Although hypomagnesemia has been associated to several neurological diseases, Mg2+ status is not regularly assessed in patients with seizures and mental disability. Our findings establish CNNM2 as an important protein for renal magnesium handling, brain development and neurological functioning, thus explaining the physiology of human disease caused by (dysfunctional) mutations in CNNM2. CNNM2 mutations should be taken into account in patients with seizures and mental disability, specifically in combination with hypomagnesemia.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
4.4
作者：
Goytain A;Quamme GA
通讯作者：
Quamme GA
DOI：
10.1152/ajprenal.00322.2013
发表时间：
2013-12-01
影响因子：
4.2
作者：
de Baaij, Jeroen H. F.;Koerkamp, Marian J. Groot;Hoenderop, Joost G. J.
通讯作者：
Hoenderop, Joost G. J.
影响因子：
4.8
作者：
de Baaij, Jeroen H. F.;Stuiver, Marchel;Hoenderop, Joost G. J.
通讯作者：
Hoenderop, Joost G. J.
影响因子：
30.8
作者：
Newton-Cheh, Christopher;Johnson, Toby;Gateva, Vesela;Tobin, Martin D.;Bochud, Murielle;Coin, Lachlan;Najjar, Samer S.;Zhao, Jing Hua;Heath, Simon C.;Eyheramendy, Susana;Papadakis, Konstantinos;Voight, Benjamin F.;Scott, Laura J.;Zhang, Feng;Farrall, Martin;Tanaka, Toshiko;Wallace, Chris;Chambers, John C.;Khaw, Kay-Tee;Nilsson, Peter;van der Harst, Pim;Polidoro, Silvia;Grobbee, Diederick E.;Onland-Moret, N. Charlotte;Bots, Michiel L.;Wain, Louise V.;Elliott, Katherine S.;Teumer, Alexander;Luan, Jian'an;Lucas, Gavin;Kuusisto, Johanna;Burton, Paul R.;Hadley, David;McArdle, Wendy L.;Brown, Morris;Dominiczak, Anna;Newhouse, Stephen J.;Samani, Nilesh J.;Webster, John;Zeggini, Eleftheria;Beckmann, Jacques S.;Bergmann, Sven;Lim, Noha;Song, Kijoung;Vollenweider, Peter;Waeber, Gerard;Waterworth, Dawn M.;Yuan, Xin;Groop, Leif;Orho-Melander, Marju;Allione, Alessandra;Di Gregorio, Alessandra;Guarrera, Simonetta;Panico, Salvatore;Ricceri, Fulvio;Romanazzi, Valeria;Sacerdote, Carlotta;Vineis, Paolo;Barroso, Ines;Sandhu, Manjinder S.;Luben, Robert N.;Crawford, Gabriel J.;Jousilahti, Pekka;Perola, Markus;Boehnke, Michael;Bonnycastle, Lori L.;Collins, Francis S.;Jackson, Anne U.;Mohlke, Karen L.;Stringham, Heather M.;Valle, Timo T.;Willer, Cristen J.;Bergman, Richard N.;Morken, Mario A.;Doering, Angela;Gieger, Christian;Illig, Thomas;Meitinger, Thomas;Org, Elin;Pfeufer, Arne;Wichmann, H. Erich;Kathiresan, Sekar;Marrugat, Jaume;O'Donnell, Christopher J.;Schwartz, Stephen M.;Siscovick, David S.;Subirana, Isaac;Freimer, Nelson B.;Hartikainen, Anna-Liisa;McCarthy, Mark I.;O'Reilly, Paul F.;Peltonen, Leena;Pouta, Anneli;de Jong, Paul E.;Snieder, Harold;van Gilst, Wiek H.;Clarke, Robert;Goel, Anuj;Hamsten, Anders;Peden, John F.;Seedorf, Udo;Syvanen, Ann-Christine;Tognoni, Giovanni;Lakatta, Edward G.;Sanna, Serena;Scheet, Paul;Schlessinger, David;Scuteri, Angelo;Doerr, Marcus;Ernst, Florian;Felix, Stephan B.;Homuth, Georg;Lorbeer, Roberto;Reffelmann, Thorsten;Rettig, Rainer;Voelker, Uwe;Galan, Pilar;Gut, Ivo G.;Hercberg, Serge;Lathrop, G. Mark;Zelenika, Diana;Deloukas, Panos;Soranzo, Nicole;Williams, Frances M.;Zhai, Guangju;Salomaa, Veikko;Laakso, Markku;Elosua, Roberto;Forouhi, Nita G.;Volzke, Henry;Uiterwaal, Cuno S.;van der Schouw, Yvonne T.;Numans, Mattijs E.;Matullo, Giuseppe;Navis, Gerjan;Berglund, Goran;Bingham, Sheila A.;Kooner, Jaspal S.;Connell, John M.;Bandinelli, Stefania;Ferrucci, Luigi;Watkins, Hugh;Spector, Tim D.;Tuomilehto, Jaakko;Altshuler, David;Strachan, David P.;Laan, Maris;Meneton, Pierre;Wareham, Nicholas J.;Uda, Manuela;Jarvelin, Marjo-Riitta;Mooser, Vincent;Melander, Olle;Loos, Ruth J. F.;Elliott, Paul;Abecasis, Goncalo R.;Caulfield, Mark;Munroe, Patricia B.
通讯作者：
Munroe, Patricia B.