Clayton, PT

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L E T T E R T O THE ED I T ORIs susceptibility to severe COVID-19 disease an inborn errorof metabolism?At the time of writing, severe Covid-19 disease has beenresponsible for 383 000 deaths worldwide (Johns Hopkinsdata). Most deaths occur in the <10% of infected individ-uals that develop respiratory failure.1 This is caused bybilateral interstitial pneumonia and acute respiratory dis-tress syndrome and leads to dependence on mechanicalventilation.2 The pathogenesis of the pneumonia ispoorly understood although the identification of a lym-phocytic endotheliitis and widespread microvascular andmacrovascular thromboembolic complications have ledto the suggestion that the virus primarily injures the vas-cular endothelium.3-5 Patients with severe disease havehigh levels of proinflammatory cytokines.6-8 An impor-tant driver of cytokine production in viral infections aswell as in autoimmune disorders is the unfolded proteinresponse in the endoplasmic reticulum.9Ellinghaus et al recently reported a genome-wide asso-ciation analysis comparing patients with respiratory failurein the SARS-CoV-2 pandemic in Italy and Spain to popula-tion derived controls.10 They detected cross-replicatingassociations with rs11385942 at chromosome 3p21.31 andrs657152 at 9q34, which were genome-wide significant(P < 5 × 10−8). Among the six genes at 3p21.31 was one,SLC6A20, which encodes the proline transporter SIT1 thatis mutated in hyperglycinuria and iminoglycinuria.11Ellinghaus et al suggested that the importance of SIT1 isbecause it interacts with angiotensin converting enzyme 2(ACE), the SARS-CoV-2 cell receptor.10,12,13 However, itcould be the protein's function in transporting proline thatis important in severe Covid-19 disease.Proline is an important intracellular osmolyte withprofound effects on protein folding.14,15 Over-expressionof a cell surface proline transporter in Escherichia colican prevent misfolding of a model protein and of con-structs containing exon 1 of huntingtin with extendedpolyamine tracts. Other osmolytes have also been shownto ameliorate defective protein folding. For example,trimethylamine N-oxide (TMAO) corrects assemblydefects of branched chain α-ketoacid decarboxylase inmaple syrup urine disease,16 reverses defective traffickingof the ΔF508 cystic fibrosis transmembrane conductanceregulator in cystic fibrosis,17 and enhances antigen pre-sentation in antigen-presenting cells.18So, it is possible that low activity of SIT1 leads to alow proline concentration at sites of protein folding,leading to an exaggerated unfolded protein response inhelper T-lymphocytes and macrophages, thereby con-tributing to a pathogenic cytokine storm. Alternatively,higher than normal SIT1 activity could lead to unusuallyhigh-proline concentrations impairing the immuneresponse. Either mechanism could contribute to theincreased morbidity and mortality. This hypothesis canbe tested by measuring the proline content of peripheralblood mononuclear cells in individuals with good andpoor outcomes of Covid-19 infection. Plasma and urineconcentrations of proline may also be different in thetwo groups. Genome sequencing projects will be able toconfirm that there are specific variants in SLC6A20 asso-ciated with poor outcome; it will be important to useexpression studies to determine whether they are gain-of-function or loss-of-function variants. There may be atherapeutic role for dietary proline supplementation orrestriction.This article does not contain any studies with humanor animal subjects performed by the author.Peter T. ClaytonGenetics and Genomic Medicine, UCL Great OrmondStreet Institute of Child Health, London, UKCorrespondencePeter T. Clayton, Genetics and Genomic Medicine, UCLGreat Ormond Street Institute of Child Health, 30Guilford Street, London WC1N 1EH, UK.Email: peter.clayton@ucl.ac.ukReceived: 6 June 2020 Revised: 26 June 2020 Accepted: 27 June 2020DOI: 10.1002/jimd.12280This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, providedthe original work is properly cited.© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.906 J Inherit Metab Dis. 2020;43:906–907.wileyonlinelibrary.com/journal/jimdORCIDPeter T. Clayton https://orcid.org/0000-0001-7592-4302REFERENCES1. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl JMed. 2020. https://doi.org/10.1056/NEJMcp2009575.2. Marini JJ, Gattinoni L. Management of COVID-19 respiratorydistress. JAMA. 2020;323:2329. https://doi.org/10.1001/jama.2020.6825.3. Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities andthrombosis in patients with COVID-19. Lancet Haematol. 2020;7:e438-e440. https://doi.org/10.1016/S2352-3026(20)30145-9.4. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infectionand endotheliitis in COVID19. Lancet. 2020;395:1417-1418.5. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vas-cular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020;383:120–128. https://doi.org/10.1056/NEJMoa2015432.6. Huang C, Wang Y, Li X, et al. Clinical features of patientsinfected with 2019 novel coronavirus in Wuhan, China. Lancet.2020;395:497-506.7. Zhou Y, Fu B, Zheng X, et al. Pathogenic T cells and inflamma-tory monocytes incite inflammatory storm in severe COVID-19patients. Natl Sci Rev. 2020;7:998-1002. https://doi.org/10.1093/nsr/nwaa041.8. Qin C, Zhou L, Hu Z, et al. Dysregulation of immune responsein patients with COVID-19 in Wuhan, China. Clin Infect Dis.2020. https://doi.org/10.1093/cid/ciaa248.9. Smith JA. Regulation of cytokine production by the unfoldedprotein response; implications for infection and autoimmunity.Front Immunol. 2018;9:422.10. Ellinghaus D, Degenhardt F, Bujanda L, et al. The ABO bloodgroup locus and a chromosome 3 gene cluster associate withSARS CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. medRxiv. 2020. https://doi.org/10.1101/2020.05.31.20114991.11. Broer S, Bailey CG, Kowalczuk S, et al. Iminoglycinuria andhyperglycinuria are discrete human phenotypes resulting fromcomplex mutations in proline and glycine transporters. J ClinInvest. 2008;118:3881-3892.12. Vuille-dit-Bille RN, Camargo SM, Emmenegger L, et al.Human intestine luminal ACE2 and amino acid transporterexpression increased by ACE-inhibitors. Amino Acids. 2015;47:693705.13. Kuba K, Imai Y, Ohto-Nakanishi T, Penninger JM. Trilogy ofACE2: a peptidase in the reninangiotensin system, a SARSreceptor, and a partner for amino acid transporters. PharmacolTher. 2010;128:119-128.14. Fisher MT. Proline to the rescue. PNAS. 2006;103:13265-13266.15. Ignatova Z, Gierasch LM. Inhibition of protein aggregation invitro and in vivo by a natural osmoprotectant. Proc Natl AcadSci USA. 2006;103(36):13357-13361.16. Song J-L, Chuang DT. Natural osmolyte trimethylamine N-oxide corrects assembly defects of mutant branched-chainα-ketoacid decarboxylase in maple syrup urine disease. J BiolChem. 2001;276:40241-40246.17. Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS,Welch WJ. Chemical chaperones correct the mutant pheno-type of the delta F508 cystic fibrosis transmembrane con-ductance regulator protein. Cell Stress Chaperones. 1996;1:117-125.18. Ghumman B, Bertram EM, Watts TH. Chemical chaperonesenhance superantigen and conventional antigen presentationby HLA-DM-deficient as well as HLA-DM-sufficient antigen-presenting cells and enhance IgG2a production in vivo. JImmunol. 1998;161:3262-3270.LETTER TO THE EDITOR 907

Is susceptibility to severe COVID-19 disease an inborn error of metabolism?

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Is susceptibility to severe COVID-19 disease an inborn error of metabolism?

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