Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism.
Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism.
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DOI：
10.1002/jbmr.4795
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发表时间：
2023-05
影响因子：
6.2
通讯作者：
Tobias, Jonathan H.
中科院分区：
文献类型：
--
作者：
Hassan, Neelam;Gregson, Celia L. L.;Tang, Haotian;van der Kamp, Marc;Leo, Paul;McInerney-Leo, Aideen M.;Zheng, Jie;Brandi, Maria Luisa;Tang, Jonathan C. Y.;Fraser, William;Stone, Michael D.;Grundberg, Elin;Brown, Matthew A.;Duncan, Emma L.;Tobias, Jonathan H.
骨质疏松症的合成代谢治疗选择仍然有限。发现新的合成代谢药物靶点的一种方法是确定极高骨量（HBM）的遗传原因。我们在英国HBM研究中调查了一个不明原因的HBM家系，这是一个全国性的HBM先证者及其亲属队列。HBM家族的全外显子组测序（WES）鉴定了GALNT 3中的一种罕见的杂合错义变体（NM_004482.4：c.1657C > T，p.Arg553Trp），适当分离。对英国HBM研究和英澳骨质疏松遗传学协会（AOGC）数据的调查显示，一名不相关的HBM患者在同一基因内存在另一种罕见的杂合变体（NM_004482. 4：c.831 T > A，p.Asp277Glu）。计算机蛋白质建模预测p.Arg553Trp会破坏盐桥相互作用，导致GALNT3不稳定，而p.Asp277Glu会破坏锰结合，从而破坏GALNT3催化功能。双等位基因功能丧失GALNT3突变改变FGF 23代谢，导致高磷血症并引起家族性肿瘤性钙质沉着症（FTC）。然而，FTC病例中的骨矿物质密度（BMD）在报告时要么正常要么偏低。GALNT3基因座的常见变异显示出全基因组范围内与腰椎、股骨颈和全身BMD的显著相关性。然而，在编码FGF23、其受体FGFR1或辅助受体klotho的基因座处未观察到与BMD的显著关联。使用来自原代人成骨细胞的表达数量性状基因座（eQTL）数据和来自UK Biobank的全基因组关联研究数据进行的孟德尔随机化分析表明，GALNT 3表达增加会降低全身、腰椎和股骨颈BMD，但对磷酸盐浓度没有影响。总之，GALNT3中罕见的杂合功能丧失变体可能导致HBM而不改变磷酸盐浓度。这些发现表明，GALNT3可能通过FGF23调节以外的途径影响BMD，其鉴定可能产生新的骨质疏松症合成代谢药物靶点。版权所有© 2023作者。《骨与矿物质研究杂志》由Wiley Periodicals LLC代表美国骨与矿物质研究学会（ASBMR）出版。
Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C > T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo‐Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt‐bridge interactions, causing instability of GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi‐allelic loss‐of‐function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome‐wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome‐wide association studies data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine, and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss‐of‐function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, the identification of which may yield novel anabolic drug targets for osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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影响因子：
2
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan N;Thompson J
通讯作者：
Thompson J
影响因子：
64.8
作者：
Fuchsberger, Christian;Flannick, Jason;Teslovich, Tanya M.;Mahajan, Anubha;Agarwala, Vineeta;Gaulton, Kyle J.;Ma, Clement;Fontanillas, Pierre;Moutsianas, Loukas;McCarthy, Davis J.;Rivas, Manuel A.;Perry, John R. B.;Sim, Xueling;Blackwell, Thomas W.;Robertson, Neil R.;Rayner, N. William;Cingolani, Pablo;Locke, Adam E.;Tajes, Juan Fernandez;Highland, Heather M.;Dupuis, Josee;Chines, Peter S.;Lindgren, Cecilia M.;Hartl, Christopher;Jackson, Anne U.;Chen, Han;Huyghe, Jeroen R.;van de Bunt, Martijn;Pearson, Richard D.;Kumar, Ashish;Mueller-Nurasyid, Martina;Grarup, Niels;Stringham, Heather M.;Gamazon, Eric R.;Lee, Jaehoon;Chen, Yuhui;Scott, Robert A.;Below, Jennifer E.;Chen, Peng;Huang, Jinyan;Go, Min Jin;Stitzel, Michael L.;Pasko, Dorota;Parker, Stephen C. J.;Varga, Tibor V.;Green, Todd;Beer, Nicola L.;Day-Williams, Aaron G.;Ferreira, Teresa;Fingerlin, Tasha;Horikoshi, Momoko;Hu, Cheng;Huh, Iksoo;Ikram, Mohammad Kamran;Kim, Bong-Jo;Kim, Yongkang;Kim, Young Jin;Kwon, Min-Seok;Lee, Juyoung;Lee, Selyeong;Lin, Keng-Han;Maxwell, Taylor J.;Nagai, Yoshihiko;Wang, Xu;Welch, Ryan P.;Yoon, Joon;Zhang, Weihua;Barzilai, Nir;Voight, Benjamin F.;Han, Bok-Ghee;Jenkinson, Christopher P.;Kuulasmaa, Teemu;Kuusisto, Johanna;Manning, Alisa;Ng, Maggie C. Y.;Palmer, Nicholette D.;Balkau, Beverley;Stancakova, Alena;Abboud, Hanna E.;Boeing, Heiner;Giedraitis, Vilmantas;Prabhakaran, Dorairaj;Gottesman, Omri;Scott, James;Carey, Jason;Kwan, Phoenix;Grant, George;Smith, Joshua D.;Neale, Benjamin M.;Purcell, Shaun;Butterworth, Adam S.;Howson, Joanna M. M.;Lee, Heung Man;Lu, Yingchang;Kwak, Soo-Heon;Zhao, Wei;Danesh, John;Lam, Vincent K. L.;Park, Kyong Soo;Saleheen, Danish;So, Wing Yee;Tam, Claudia H. T.;Afzal, Uzma;Aguilar, David;Arya, Rector;Aung, Tin;Chan, Edmund;Navarro, Carmen;Cheng, Ching-Yu;Palli, Domenico;Correa, Adolfo;Curran, Joanne E.;Rybin, Denis;Farook, Vidya S.;Fowler, Sharon P.;Freedman, Barry I.;Griswold, Michael;Hale, Daniel Esten;Hicks, Pamela J.;Khor, Chiea-Chuen;Kumar, Satish;Lehne, Benjamin;Thuillier, Dorothee;Lim, Wei Yen;Liu, Jianjun;van der Schouw, Yvonne T.;Loh, Marie;Musani, Solomon K.;Puppala, Sobha;Scott, William R.;Yengo, Loic;Tan, Sian-Tsung;Taylor, Herman A., Jr.;Thameem, Farook;Wilson, Gregory, Sr.;Wong, Tien Yin;Njolstad, Pal Rasmus;Levy, Jonathan C.;Mangino, Massimo;Bonnycastle, Lori L.;Schwarzmayr, Thomas;Fadista, Joao;Surdulescu, Gabriela L.;Herder, Christian;Groves, Christopher J.;Wieland, Thomas;Bork-Jensen, Jette;Brandslund, Ivan;Christensen, Cramer;Koistinen, Heikki A.;Doney, Alex S. F.;Kinnunen, Leena;Esko, Tonu;Farmer, Andrew J.;Hakaste, Liisa;Hodgkiss, Dylan;Kravic, Jasmina;Lyssenko, Valeriya;Hollensted, Mette;Jorgensen, Marit E.;Jorgensen, Torben;Ladenvall, Claes;Justesen, Johanne Marie;Karajamaki, Annemari;Kriebel, Jennifer;Rathmann, Wolfgang;Lannfelt, Lars;Lauritzen, Torsten;Narisu, Narisu;Linneberg, Allan;Melander, Olle;Milani, Lili;Neville, Matt;Orho-Melander, Marju;Qi, Lu;Qi, Qibin;Roden, Michael;Rolandsson, Olov;Swift, Amy;Rosengren, Anders H.;Stirrups, Kathleen;Wood, Andrew R.;Mihailov, Evelin;Blancher, Christine;Carneiro, Mauricio O.;Maguire, Jared;Poplin, Ryan;Shakir, Khalid;Fennell, Timothy;DePristo, Mark;de Angelis, Martin Hrabe;Deloukas, Panos;Gjesing, Anette P.;Jun, Goo;Nilsson, Peter;Murphy, Jacquelyn;Onofrio, Robert;Thorand, Barbara;Hansen, Torben;Meisinger, Christa;Hu, Frank B.;Isomaa, Bo;Karpe, Fredrik;Liang, Liming;Peters, Annette;Huth, Cornelia;O'Rahilly, Stephen P.;Palmer, Colin N. A.;Pedersen, Oluf;Rauramaa, Rainer;Tuomilehto, Jaakko;Salomaa, Veikko;Watanabe, Richard M.;Syvanen, Ann-Christine;Bergman, Richard N.;Bharadwaj, Dwaipayan;Bottinger, Erwin P.;Cho, Yoon Shin;Chandak, Giriraj R.;Chan, Juliana C. N.;Chia, Kee Seng;Daly, Mark J.;Ebrahim, Shah B.;Langenberg, Claudia;Elliott, Paul;Jablonski, Kathleen A.;Lehman, Donna M.;Jia, Weiping;Ma, Ronald C. W.;Pollin, Toni I.;Sandhu, Manjinder;Tandon, Nikhil;Froguel, Philippe;Barroso, Ines;Teo, Yik Ying;Zeggini, Eleftheria;Loos, Ruth J. F.;Small, Kerrin S.;Ried, Janina S.;DeFronzo, Ralph A.;Grallert, Harald;Glaser, Benjamin;Metspalu, Andres;Wareham, Nicholas J.;Walker, Mark;Banks, Eric;Gieger, Christian;Ingelsson, Erik;Im, Hae Kyung;Illig, Thomas;Franks, Paul W.;Buck, Gemma;Trakalo, Joseph;Buck, David;Prokopenko, Inga;Magi, Reedik;Lind, Lars;Farjoun, Yossi;Owen, Katharine R.;Gloyn, Anna L.;Strauch, Konstantin;Tuomi, Tiinamaija;Kooner, Jaspal Singh;Lee, Jong-Young;Park, Taesung;Donnelly, Peter;Morris, Andrew D.;Hattersley, Andrew T.;Bowden, Donald W.;Collins, Francis S.;Atzmon, Gil;Chambers, John C.;Spector, Timothy D.;Laakso, Markku;Strom, Tim M.;Bell, Graeme I.;Blangero, John;Duggirala, Ravindranath;Tai, E. Shyong;McVean, Gilean;Hanis, Craig L.;Wilson, James G.;Seielstad, Mark;Frayling, Timothy M.;Meigs, James B.;Cox, Nancy J.;Sladek, Rob;Lander, Eric S.;Gabriel, Stacey;Burtt, Noel P.;Mohlke, Karen L.;Meitinger, Thomas;Groop, Leif;Abecasis, Goncalo;Florez, Jose C.;Scott, Laura J.;Morris, Andrew P.;Kang, Hyun Min;Boehnke, Michael;Altshuler, David;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
9.8
作者：
Flannick J;Fuchsberger C;Mahajan A;Teslovich TM;Agarwala V;Gaulton KJ;Caulkins L;Koesterer R;Ma C;Moutsianas L;McCarthy DJ;Rivas MA;Perry JRB;Sim X;Blackwell TW;Robertson NR;Rayner NW;Cingolani P;Locke AE;Tajes JF;Highland HM;Dupuis J;Chines PS;Lindgren CM;Hartl C;Jackson AU;Chen H;Huyghe JR;van de Bunt M;Pearson RD;Kumar A;Müller-Nurasyid M;Grarup N;Stringham HM;Gamazon ER;Lee J;Chen Y;Scott RA;Below JE;Chen P;Huang J;Go MJ;Stitzel ML;Pasko D;Parker SCJ;Varga TV;Green T;Beer NL;Day-Williams AG;Ferreira T;Fingerlin T;Horikoshi M;Hu C;Huh I;Ikram MK;Kim BJ;Kim Y;Kim YJ;Kwon MS;Lee J;Lee S;Lin KH;Maxwell TJ;Nagai Y;Wang X;Welch RP;Yoon J;Zhang W;Barzilai N;Voight BF;Han BG;Jenkinson CP;Kuulasmaa T;Kuusisto J;Manning A;Ng MCY;Palmer ND;Balkau B;Stančáková A;Abboud HE;Boeing H;Giedraitis V;Prabhakaran D;Gottesman O;Scott J;Carey J;Kwan P;Grant G;Smith JD;Neale BM;Purcell S;Butterworth AS;Howson JMM;Lee HM;Lu Y;Kwak SH;Zhao W;Danesh J;Lam VKL;Park KS;Saleheen D;So WY;Tam CHT;Afzal U;Aguilar D;Arya R;Aung T;Chan E;Navarro C;Cheng CY;Palli D;Correa A;Curran JE;Rybin D;Farook VS;Fowler SP;Freedman BI;Griswold M;Hale DE;Hicks PJ;Khor CC;Kumar S;Lehne B;Thuillier D;Lim WY;Liu J;Loh M;Musani SK;Puppala S;Scott WR;Yengo L;Tan ST;Taylor HA;Thameem F;Wilson G;Wong TY;Njølstad PR;Levy JC;Mangino M;Bonnycastle LL;Schwarzmayr T;Fadista J;Surdulescu GL;Herder C;Groves CJ;Wieland T;Bork-Jensen J;Brandslund I;Christensen C;Koistinen HA;Doney ASF;Kinnunen L;Esko T;Farmer AJ;Hakaste L;Hodgkiss D;Kravic J;Lyssenko V;Hollensted M;Jørgensen ME;Jørgensen T;Ladenvall C;Justesen JM;Käräjämäki A;Kriebel J;Rathmann W;Lannfelt L;Lauritzen T;Narisu N;Linneberg A;Melander O;Milani L;Neville M;Orho-Melander M;Qi L;Qi Q;Roden M;Rolandsson O;Swift A;Rosengren AH;Stirrups K;Wood AR;Mihailov E;Blancher C;Carneiro MO;Maguire J;Poplin R;Shakir K;Fennell T;DePristo M;de Angelis MH;Deloukas P;Gjesing AP;Jun G;Nilsson P;Murphy J;Onofrio R;Thorand B;Hansen T;Meisinger C;Hu FB;Isomaa B;Karpe F;Liang L;Peters A;Huth C;O'Rahilly SP;Palmer CNA;Pedersen O;Rauramaa R;Tuomilehto J;Salomaa V;Watanabe RM;Syvänen AC;Bergman RN;Bharadwaj D;Bottinger EP;Cho YS;Chandak GR;Chan JC;Chia KS;Daly MJ;Ebrahim SB;Langenberg C;Elliott P;Jablonski KA;Lehman DM;Jia W;Ma RCW;Pollin TI;Sandhu M;Tandon N;Froguel P;Barroso I;Teo YY;Zeggini E;Loos RJF;Small KS;Ried JS;DeFronzo RA;Grallert H;Glaser B;Metspalu A;Wareham NJ;Walker M;Banks E;Gieger C;Ingelsson E;Im HK;Illig T;Franks PW;Buck G;Trakalo J;Buck D;Prokopenko I;Mägi R;Lind L;Farjoun Y;Owen KR;Gloyn AL;Strauch K;Tuomi T;Kooner JS;Lee JY;Park T;Donnelly P;Morris AD;Hattersley AT;Bowden DW;Collins FS;Atzmon G;Chambers JC;Spector TD;Laakso M;Strom TM;Bell GI;Blangero J;Duggirala R;Tai ES;McVean G;Hanis CL;Wilson JG;Seielstad M;Frayling TM;Meigs JB;Cox NJ;Sladek R;Lander ES;Gabriel S;Mohlke KL;Meitinger T;Groop L;Abecasis G;Scott LJ;Morris AP;Kang HM;Altshuler D;Burtt NP;Florez JC;Boehnke M;McCarthy MI
通讯作者：
McCarthy MI
影响因子：
6.2
作者：
Burge, Russel;Dawson-Hughes, Bess;Tosteson, Anna
通讯作者：
Tosteson, Anna
影响因子：
3.5
作者：
Barbieri, Anna Maria;Filopanti, Marcello;Beck-Peccoz, Paolo
通讯作者：
Beck-Peccoz, Paolo