Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration

被引：2

作者：

Groeneweg, Stefan ^{[1
]}

van Geest, Ferdy S. ^{[1
]}

Martin, Mariano ^{[2
,3
]}

Dias, Mafalda ^{[4
,5
,6
]}

Frazer, Jonathan ^{[4
,5
,6
]}

Medina-Gomez, Carolina ^{[7
]}

Sterenborg, Rosalie B. T. M. ^{[1
,8
]}

Wang, Hao ^{[9
]}

Dolcetta-Capuzzo, Anna ^{[1
]}

de Rooij, Linda J. ^{[1
]}

Teumer, Alexander ^{[10
,11
]}

Abaci, Ayhan ^{[12
]}

van den Akker, Erica L. T. ^{[13
]}

Ambegaonkar, Gautam P. ^{[14
]}

Armour, Christine M. ^{[15
,16
]}

Bacos, Iiuliu ^{[17
]}

Bakhtiani, Priyanka ^{[18
,98
]}

Barca, Diana ^{[19
]}

Bauer, Andrew J. ^{[20
]}

van den Berg, Sjoerd A. A. ^{[21
]}

van den Berge, Amanda ^{[1
]}

Bertini, Enrico ^{[22
]}

van Beynum, Ingrid M. ^{[23
]}

Brunetti-Pierri, Nicola ^{[24
,25
,26
]}

Brunner, Doris ^{[27
]}

Cappa, Marco ^{[28
]}

Cappuccio, Gerarda ^{[24
,29
,30
]}

Castellotti, Barbara ^{[31
]}

Castiglioni, Claudia ^{[32
]}

Chatterjee, Krishna ^{[33
]}

Chesover, Alexander ^{[34
,35
,99
]}

Christian, Peter ^{[36
]}

van der Spek, Jet ^{[37
]}

de Coo, Irenaeus F. M. ^{[38
]}

Coutant, Regis ^{[39
]}

Craiu, Dana ^{[19
]}

Crock, Patricia ^{[40
]}

Degoede, Christian ^{[41
]}

Demir, Korcan ^{[12
]}

Dewey, Cheyenne ^{[42
]}

Dica, Alice ^{[19
]}

Dimitri, Paul ^{[43
]}

Dremmen, Marjolein H. G. ^{[44
]}

Dubey, Rachana ^{[45
]}

Enderli, Anina ^{[46
]}

Fairchild, Jan ^{[47
]}

Gallichan, Jonathan ^{[48
]}

Garibaldi, Luigi ^{[49
]}

George, Belinda ^{[50
]}

Gevers, Evelien F. ^{[51
]}

机构：

[1] Erasmus MC, Acad Ctr Thyroid Dis, Dept Internal Med, Rotterdam, Netherlands

[2] Natl Univ Cordoba, Fac Chem Sci, Dept Clin Biochem, CIBICI CONICET, Cordoba, Argentina

[3] Barcelona Inst Sci & Technol, Inst Bioengn Catalonia IBEC, Barcelona, Spain

[4] Harvard Med Sch, Dept Syst Biol, Boston, MA USA

[5] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Barcelona, Spain

[6] Univ Pompeu Fabra UPF, Barcelona, Spain

[7] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[8] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Div Endocrinol, Nijmegen, Netherlands

[9] Univ Calif San Diego, Ctr Multimodal Imaging & Genet, La Jolla, CA USA

[10] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany

[11] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany

[12] Dokuz Eylul Univ, Fac Med, Div Pediat Endocrinol, Izmir, Turkiye

[13] Erasmus MC, Sophia Childrens Hosp, Dept Paediat, Div Endocrinol, Rotterdam, Netherlands

[14] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Dept Paediat Neurol, Cambridge, England

[15] Childrens Hosp Eastern Ontario Ottawa, Reg Genet Program, Ottawa, ON, Canada

[16] Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada

[17] Univ Med & Farm Timisoara, Timisoara 300029, Romania

[18] Univ Louisville, Louisville, KY USA

[19] Carol Davila Univ Med & Pharm Bucharest, Dept Clin Neurosci, Paediat Neurol Discipline 2, Bucharest, Romania

[20] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA USA

[21] Erasmus MC, Dept Internal Med, Diagnost Lab Endocrinol, Rotterdam, Netherlands

[22] Bambino Gesu Childrens Res Hosp, Res Unit Neuromuscular & Neurodegenerat Disorders, IRCCS, Rome, Italy

[23] Erasmus MC, Sophia Childrens Hosp, Dept Pediat, Div Pediat Cardiol, Rotterdam, Netherlands

[24] Univ Naples Federico II, Dept Translat Med, Naples, Italy

[25] Telethon Inst Genet & Med TIGEM, Naples, Italy

[26] Univ Naples Federico II, Sch Adv Studies, Genom & Expt Med Program, Scuola Super Merid SSM, Naples, Italy

[27] Gottfried V Preyers Hosp Sick Children, Vienna, Austria

[28] Bambino Gesu Pediat Hosp, Res Area Innovat Therapies Endocrinopathies, IRCCS, Rome, Italy

[29] Neurol Res Inst, Houston, TX USA

[30] Baylor Coll Med, Houston, TX USA

[31] Fdn IRCCS Ist Neurol Carlo Besta, Unit Med Genet & Neurogenet, Milan, Italy

[32] Finis Terrae Univ, Sch Med, Santiago, Chile

[33] Univ Cambridge, Wellcome Trust Med Res Council, Inst Metab Sci, Cambridge, England

[34] Univ Toronto, Hosp Sick Children, Dept Paediat, Toronto, ON M5G 1H4, Canada

[35] Univ Toronto, Dept Paediat, Toronto, ON M5G 1X8, Canada

[36] East Kent Hosp Univ NHS Fdn Trust, Ashford, England

[37] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Med Ctr Radboudumc, Dept Human Genet, Nijmegen, Netherlands

[38] Maastricht Univ, MHeNs Sch Mental Hlth & Neurosci, Dept Toxicogen, Unit Clin Genom, Maastricht, Netherlands

[39] Univ Hosp, Dept Pediat Endocrinol & Diabetol, Angers, France

[40] Univ Newcastle, John Hunter Childrens Hosp, Hunter Med Res Inst, New Lambton, NSW, Australia

[41] Lancashire Teaching Hosp NHS Trust, Dept Paediat Neurol, Clin Res Facil, Preston, Lancs, England

[42] MultiCare Hlth Syst, Mary Bridge Childrens Hosp, Genom Inst, Tacoma, WA 98415 USA

[43] Univ Sheffield, Dept Oncol & Metab, Western Bank, Sheffield S10 2TH, England

[44] Erasmus MC, Sophias Children Hosp, Div Paediat Radiol, Rotterdam, Netherlands

[45] Medanta Superspecial Hosp, Indore, India

[46] Univ Zurich, Univ Childrens Hosp, Dept Neuropediat, Zurich, Switzerland

[47] Womens & Childrens Hosp, Dept Diabet & Endocrinol, North Adelaide, SA 5066, Australia

[48] Plymouth Hosp NHS Trust, Plymouth, England

[49] UPMC Childrens Hosp Pittsburgh, Pittsburgh, PA USA

[50] St Johns Med Coll Hosp, Dept Endocrinol, Bengaluru, India

来源：

NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期

基金：

英国惠康基金;

关键词：

HERNDON-DUDLEY-SYNDROME; MONOCARBOXYLATE TRANSPORTER-8; PSYCHOMOTOR RETARDATION; CELLULAR UPTAKE; MUTATIONS; DEFICIENCY; ACID; IDENTIFICATION; ASSOCIATION; PROTEINS;

D O I：

10.1038/s41467-025-56628-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in similar to 400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

引用

页数：21

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