Structure-Function Relationship of Homogentisate 1,2-dioxygenase: Understanding the Genotype-Phenotype Correlations in the Rare Genetic Disease Alkaptonuria

Page: [380 - 392] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs, which occurs because the homogentisate 1,2-dioxygenase (HGD) enzyme is not functional due to gene variants. Over time, HGA oxidation and accumulation cause the formation of the ochronotic pigment, a deposit that provokes tissue degeneration and organ malfunction. Here, we report a comprehensive review of the variants so far reported, the structural studies on the molecular consequences of protein stability and interaction, and molecular simulations for pharmacological chaperones as protein rescuers. Moreover, evidence accumulated so far in alkaptonuria research will be re-proposed as the bases for a precision medicine approach in a rare disease.

Graphical Abstract

[1]
Mistry, J.B.; Bukhari, M.; Taylor, A.M. Alkaptonuria. Rare Dis., 2013, 18(1), e27475.
[http://dx.doi.org/10.4161/rdis.27475] [PMID: 25003018]
[2]
Zatkova, A.; Ranganath, L.; Kadasi, L. Alkaptonuria: Current perspectives. Appl. Clin. Genet., 2020, 13, 37-47.
[http://dx.doi.org/10.2147/TACG.S186773] [PMID: 32158253]
[3]
Zatkova, A.; Sedlackova, T.; Radvansky, J.; Polakova, H.; Nemethova, M.; Aquaron, R.; Dursun, I.; Usher, J.L.; Kadasi, L. Identification of 11 novel homogentisate 1,2 dioxygenase variants in Alkaptonuria patients and establishment of a novel LOVD-Based HGD mutation database. JIMD Rep., 2012, 4, 55-65.
[http://dx.doi.org/10.1007/8904_2011_68] [PMID: 23430897]
[4]
Benedek, T.G. Rudolph virchow on ochronosis. Arthritis Rheum., 1966, 9(1), 66-71.
[http://dx.doi.org/10.1002/art.1780090108] [PMID: 4952902]
[5]
Fernández-Cañón, J.M.; Peñalva, M.A. Molecular characterization of a gene encoding a homogentisate dioxygenase from Aspergillus nidulans and identification of its human and plant homologues. J. Biol. Chem., 1995, 270(36), 21199-21205.
[http://dx.doi.org/10.1074/jbc.270.36.21199] [PMID: 7673153]
[6]
Ranganath, L.R.; Milan, A.M.; Hughes, A.T.; Khedr, M.; Davison, A.S.; Shweihdi, E.; Norman, B.P.; Hughes, J.H.; Bygott, H.; Luangrath, E.; Fitzgerald, R.; Psarelli, E.E.; Kan, C.; Laan, D.; Olsson, B.; Rudebeck, M.; Mankowitz, L.; Sireau, N.; Arnoux, J.B.; Le Quan Sang, K.H.; Jarvis, J.C.; Genovese, F.; Braconi, D.; Santucci, A.; Zatkova, A.; Glasova, H. Stančík, R.; Imrich, R.; Rhodes, N.P.; Gallagher, J.A. Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria. J. Inherit. Metab. Dis., 2020, 43(4), 737-747.
[http://dx.doi.org/10.1002/jimd.12181] [PMID: 31609457]
[7]
Davison, A.S.; Milan, A.M.; Gallagher, J.A.; Ranganath, L.R. Acute fatal metabolic complications in alkaptonuria. J. Inherit. Metab. Dis., 2016, 39(2), 203-210.
[http://dx.doi.org/10.1007/s10545-015-9902-0] [PMID: 26596578]
[8]
Bernini, A.; Petricci, E.; Atrei, A.; Baratto, M.C.; Manetti, F.; Santucci, A. A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria. Sci. Rep., 2021, 11(1), 22562.
[http://dx.doi.org/10.1038/s41598-021-01670-z] [PMID: 34799606]
[9]
Hegde, S.D. D, S.R.; B M, M.; Rao, E.S.; Hussain, P.S.B. Alkaptonuric arthropathy with periprosthetic fracture: A case report. J. Clin. Diagn. Res., 2014, 8(3), 176-178.
[http://dx.doi.org/10.7860/JCDR/2014/7740.4157] [PMID: 24783127]
[10]
Craide, F.H.; Mariano, P.C.; de Castro, C.G.C.; da Fonseca, J.S.B.M.; Fernandez, N.M.; de Mene, Y.S.L. Alkaptonuria - Case report. An. Bras. Dermatol., 2014, 89(5), 799-801.
[11]
Ebrahim, I.C.; Hoang, T.D.; Vietor, N.O.; Schacht, J.P.; Shakir, M.K.M. Dilemmas in the diagnosis and management of osteoporosis in a patient with alkaptonuria: Successful treatment with teriparatide. Clin. Case Rep., 2022, 10(12), e6729.
[http://dx.doi.org/10.1002/ccr3.6729] [PMID: 36583204]
[12]
Vaz Ferreira, V.; Pedro, P.G.; Fiarresga, A. Alkaptonuria: A rare cause of severe aortic stenosis treated by transcatheter aortic valve replacement. Rev. Port. Cardiol., 2023, 2023, S0870-2551(23)00004-5.
[http://dx.doi.org/10.1016/j.repc.2023.01.002] [PMID: 36608903]
[13]
Ranganath, L.R.; Timmis, O.G.; Gallagher, J.A. Progress in Alkaptonuria - are we near to an effective therapy? J. Inherit. Metab. Dis., 2015, 38(5), 787-789.
[http://dx.doi.org/10.1007/s10545-015-9888-7] [PMID: 26280757]
[14]
Xu, H.; Wang, J.; Chen, F.; Hong, Z.; Zhang, X.; Ji, X.; Shao, D. Ochronotic arthritis of bilateral knees: A case report. Int. J. Clin. Exp. Med., 2015, 8(5), 8185-8189.
[PMID: 26221390]
[15]
Al-Ajlouni, J.M.; Alisi, M.S.; Yasin, M.S.; Khanfar, A.; Hamdan, M.; Halaweh, A.A.; Al Hawamdeh, H.; Elessi, K.; Alsbou, M.S. Long-term outcomes of the knee and hip arthroplasties in patients with alkaptonuria. Arthroplast. Today, 2020, 6(4), 689-693.
[http://dx.doi.org/10.1016/j.artd.2020.07.037] [PMID: 32875021]
[16]
Millucci, L.; Ghezzi, L.; Bernardini, G.; Braconi, D.; Lupetti, P.; Perfetto, F.; Orlandini, M.; Santucci, A. Diagnosis of secondary amyloidosis in alkaptonuria. Diagn. Pathol., 2014, 9(1), 185.
[http://dx.doi.org/10.1186/s13000-014-0185-9] [PMID: 25567001]
[17]
Millucci, L.; Braconi, D.; Bernardini, G.; Lupetti, P.; Rovensky, J.; Ranganath, L.; Santucci, A. Amyloidosis in alkaptonuria. J. Inherit. Metab. Dis., 2015, 38(5), 797-805.
[http://dx.doi.org/10.1007/s10545-015-9842-8] [PMID: 25868666]
[18]
Millucci, L; Spreafico, A; Tinti, L; Braconi, D; Ghezzi, L; Paccagnini, E Alkaptonuria is a novel human secondary amyloidogenic disease. Biochim Biophys Acta., 1822, 1822(11), 1682-91.
[http://dx.doi.org/10.1016/j.bbadis.2012.07.011]
[19]
Suwannarat, P.; O’Brien, K.; Perry, M.B.; Sebring, N.; Bernardini, I.; Kaiser-Kupfer, M.I.; Rubin, B.I.; Tsilou, E.; Gerber, L.H.; Gahl, W.A. Use of nitisinone in patients with alkaptonuria. Metabolism, 2005, 54(6), 719-728.
[http://dx.doi.org/10.1016/j.metabol.2004.12.017] [PMID: 15931605]
[20]
Lock, E.; Ranganath, L.R.; Timmis, O. The role of nitisinone in tyrosine pathway disorders. Curr. Rheumatol. Rep., 2014, 16(11), 457.
[http://dx.doi.org/10.1007/s11926-014-0457-0] [PMID: 25266991]
[21]
Hanika, C.; Hornphutkul, P.; Ntrone, E.J.I.; Onique, M.; Erry, B.P.; Sa, I. Natural History of Alkaptonuria. N. Engl. J. Med., 2002, 347(26), 2111-21.
[22]
Introne, W.J.; Perry, M.B.; Troendle, J.; Tsilou, E.; Kayser, M.A.; Suwannarat, P.; O’Brien, K.E.; Bryant, J.; Sachdev, V.; Reynolds, J.C.; Moylan, E.; Bernardini, I.; Gahl, W.A. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol. Genet. Metab., 2011, 103(4), 307-314.
[http://dx.doi.org/10.1016/j.ymgme.2011.04.016] [PMID: 21620748]
[23]
Suwannarat, P.; O’Brien, K.; Perry, M.B.; Sebring, N.; Bernardini, I.; Kaiser-Kupfer, M.I.; Rubin, B.I.; Tsilou, E.; Gerber, L.H.; Gahl, W.A. Use of nitisinone in patients with alkaptonuria. Metabolism, 2005, 54(6), 719-728.
[http://dx.doi.org/10.1016/j.metabol.2004.12.017] [PMID: 15931605]
[24]
Norman, B.P.; Davison, A.S.; Hughes, J.H.; Sutherland, H.; Wilson, P.J.M.; Berry, N.G.; Hughes, A.T.; Milan, A.M.; Jarvis, J.C.; Roberts, N.B.; Ranganath, L.R.; Bou-Gharios, G.; Gallagher, J.A. Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism. Genes Dis., 2022, 9(4), 1129-1142.
[http://dx.doi.org/10.1016/j.gendis.2021.02.007] [PMID: 35685462]
[25]
Olsson, B.; Cox, T.F.; Psarelli, E.E.; Szamosi, J.; Hughes, A.T.; Milan, A.M.; Hall, A.K.; Rovensky, J.; Ranganath, L.R. Relationship between serum concentrations of nitisinone and its effect on homogentisic acid and tyrosine in patients with Alkaptonuria. JIMD Rep., 2015, 24, 21-27.
[http://dx.doi.org/10.1007/8904_2015_412] [PMID: 25772318]
[26]
Ranganath, L.R.; Milan, A.M.; Hughes, A.T.; Dutton, J.J.; Fitzgerald, R.; Briggs, M.C.; Bygott, H.; Psarelli, E.E.; Cox, T.F.; Gallagher, J.A.; Jarvis, J.C.; van Kan, C.; Hall, A.K.; Laan, D.; Olsson, B.; Szamosi, J.; Rudebeck, M.; Kullenberg, T.; Cronlund, A.; Svensson, L.; Junestrand, C.; Ayoob, H.; Timmis, O.G.; Sireau, N.; Le Quan Sang, K.H.; Genovese, F.; Braconi, D.; Santucci, A.; Nemethova, M.; Zatkova, A.; McCaffrey, J.; Christensen, P.; Ross, G.; Imrich, R.; Rovensky, J. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): An international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann. Rheum. Dis., 2016, 75(2), 362-367.
[http://dx.doi.org/10.1136/annrheumdis-2014-206033] [PMID: 25475116]
[27]
Laschi, M.; Bernardini, G.; Dreassi, E.; Millucci, L.; Geminiani, M.; Braconi, D.; Marzocchi, B.; Botta, M.; Manetti, F.; Santucci, A. Inhibition of para-hydroxyphenylpyruvate dioxygenase by analogues of the herbicide nitisinone as a strategy to decrease homogentisic acid levels, the causative agent of alkaptonuria. ChemMedChem, 2016, 11(7), 674-678.
[http://dx.doi.org/10.1002/cmdc.201500578] [PMID: 26947423]
[28]
Ranganath, L.R.; Khedr, M.; Milan, A.M.; Davison, A.S.; Hughes, A.T.; Usher, J.L.; Taylor, S.; Loftus, N.; Daroszewska, A.; West, E.; Jones, A.; Briggs, M.; Fisher, M.; McCormick, M.; Judd, S.; Vinjamuri, S.; Griffin, R.; Psarelli, E.E.; Cox, T.F.; Sireau, N.; Dillon, J.P.; Devine, J.M.; Hughes, G.; Harrold, J.; Barton, G.J.; Jarvis, J.C.; Gallagher, J.A. Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre. Mol. Genet. Metab., 2018, 125(1-2), 127-134.
[http://dx.doi.org/10.1016/j.ymgme.2018.07.011] [PMID: 30055994]
[29]
Ranganath, L.R.; Milan, A.M.; Hughes, A.T.; Davison, A.S.; Khedr, M.; Norman, B.P.; Bou-Gharios, G.; Gallagher, J.A.; Gornall, M.; Jackson, R.; Imrich, R.; Rovensky, J.; Rudebeck, M.; Olsson, B. Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria. Mol. Genet. Metab. Rep., 2022, 30, 100846.
[http://dx.doi.org/10.1016/j.ymgmr.2022.100846] [PMID: 35242577]
[30]
Ranganath, L.R.; Milan, A.M.; Hughes, A.T.; Davison, A.S. M, K.; Norman, B.P.; Bou-Gharios, G.; Gallagher, J.A.; Imrich, R.; Arnoux, J.B.; Rudebeck, M.; Olsson, B. Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria. Sci. Rep., 2022, 12(1), 16083.
[http://dx.doi.org/10.1038/s41598-022-20424-z] [PMID: 36167967]
[31]
White, A.; C., Tchan; M., Nitisinone-Induced Keratopathy in Alkaptonuria: A challenging diagnosis despite clinical suspicion. JIMD Rep., 2018, 40, 7-9.
[http://dx.doi.org/10.1007/8904_2017_56] [PMID: 28879639]
[32]
Ranganath, L.R.; Sireau, N. Clinical development innovation in rare diseases: overcoming barriers to successful delivery of a randomised clinical trial in alkaptonuria-a mini-review. Orphanet J. Rare Dis., 2023, 18(1), 1.
[http://dx.doi.org/10.1186/s13023-022-02606-0] [PMID: 36600285]
[33]
Ranganath, L.R.; Psarelli, E.E.; Arnoux, J.B.; Braconi, D.; Briggs, M.; Bröijersén, A.; Loftus, N.; Bygott, H.; Cox, T.F.; Davison, A.S.; Dillon, J.P.; Fisher, M.; FitzGerald, R.; Genovese, F.; Glasova, H.; Hall, A.K.; Hughes, A.T.; Hughes, J.H.; Imrich, R.; Jarvis, J.C.; Khedr, M.; Laan, D.; Le Quan Sang, K.H.; Luangrath, E. Lukáčová, O.; Milan, A.M.; Mistry, A.; Mlynáriková, V.; Norman, B.P.; Olsson, B.; Rhodes, N.P.; Rovenský, J.; Rudebeck, M.; Santucci, A.; Shweihdi, E.; Scott, C.; Sedláková, J.; Sireau, N.; Stančík, R.; Szamosi, J.; Taylor, S.; van Kan, C.; Vinjamuri, S.; Vrtíková, E.; Webb, C.; West, E.; Záňová, E.; Zatkova, A.; Gallagher, J.A. Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): An international, multicentre, open-label, randomised controlled trial. Lancet Diabetes Endocrinol., 2020, 8(9), 762-772.
[http://dx.doi.org/10.1016/S2213-8587(20)30228-X] [PMID: 32822600]
[34]
Grasso, D.; Geminiani, M.; Galderisi, S.; Iacomelli, G.; Peruzzi, L.; Marzocchi, B.; Santucci, A.; Bernini, A. Untargeted NMR metabolomics reveals alternative biomarkers and pathways in Alkaptonuria. Int. J. Mol. Sci., 2022, 23(24), 15805.
[http://dx.doi.org/10.3390/ijms232415805] [PMID: 36555443]
[35]
Davison, A.S.; Strittmatter, N.; Sutherland, H.; Hughes, A.T.; Hughes, J.; Bou-Gharios, G.; Milan, A.M.; Goodwin, R.J.A.; Ranganath, L.R.; Gallagher, J.A. Assessing the effect of nitisinone induced hypertyrosinaemia on monoamine neurotransmitters in brain tissue from a murine model of alkaptonuria using mass spectrometry imaging. Metabolomics, 2019, 15(5), 68.
[http://dx.doi.org/10.1007/s11306-019-1531-4] [PMID: 31037385]
[36]
Norman, B.P.; Davison, A.S.; Hughes, J.H.; Sutherland, H.; Wilson, P.J.M.; Berry, N.G.; Hughes, A.T.; Milan, A.M.; Jarvis, J.C.; Roberts, N.B.; Ranganath, L.R.; Bou-Gharios, G.; Gallagher, J.A. Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism. Genes Dis., 2022, 9(4), 1129-1142.
[http://dx.doi.org/10.1016/j.gendis.2021.02.007] [PMID: 35685462]
[37]
Zatkova, A.; Olsson, B.; Ranganath, L.R.; Imrich, R. Analysis of the phenotype differences in siblings with Alkaptonuria. Metabolites, 2022, 12(10), 990.
[http://dx.doi.org/10.3390/metabo12100990] [PMID: 36295892]
[38]
Spiga, O.; Cicaloni, V.; Bernini, A.; Zatkova, A.; Santucci, A. ApreciseKUre: An approach of precision medicine in a rare disease. BMC Med. Inform. Decis. Mak., 2017, 17(1), 42.
[http://dx.doi.org/10.1186/s12911-017-0438-0] [PMID: 28410607]
[39]
Borowski, T.; Georgiev, V.; Siegbahn, P.E.M. Catalytic reaction mechanism of homogentisate dioxygenase: A hybrid DFT study. J. Am. Chem. Soc., 2005, 127(49), 17303-17314.
[http://dx.doi.org/10.1021/ja054433j] [PMID: 16332080]
[40]
Timm, D.E.; Titus, G.P.; Mueller, H.A.; Burgner, J.; Rodríguez de Córdoba, S.; Peñalva, M.A. Crystal structure of human homogentisate dioxygenase. Nat. Struct. Biol., 2000, 7(7), 542-546.
[http://dx.doi.org/10.1038/76756] [PMID: 10876237]
[41]
Jeoung, J.H.; Bommer, M.; Lin, T.Y.; Dobbek, H. Visualizing the substrate-, superoxo-, alkylperoxo-, and product-bound states at the nonheme Fe(II) site of homogentisate dioxygenase. Proc. Natl. Acad. Sci. USA, 2013, 110(31), 12625-12630.
[http://dx.doi.org/10.1073/pnas.1302144110] [PMID: 23858455]
[42]
Bernini, A.; Galderisi, S.; Spiga, O.; Bernardini, G.; Niccolai, N.; Manetti, F.; Santucci, A. Toward a generalized computational workflow for exploiting transient pockets as new targets for small molecule stabilizers: Application to the homogentisate 1,2-dioxygenase mutants at the base of rare disease Alkaptonuria. Comput. Biol. Chem., 2017, 70, 133-141.
[http://dx.doi.org/10.1016/j.compbiolchem.2017.08.008] [PMID: 28869836]
[43]
Varrazzo, D.; Bernini, A.; Spiga, O.; Ciutti, A.; Chiellini, S.; Venditti, V.; Bracci, L.; Niccolai, N. Three-dimensional computation of atom depth in complex molecular structures. Bioinformatics, 2005, 21(12), 2856-2860.
[http://dx.doi.org/10.1093/bioinformatics/bti444] [PMID: 15827080]
[44]
Bottini, S.; Bernini, A.; De Chiara, M.; Garlaschelli, D.; Spiga, O.; Dioguardi, M.; Vannuccini, E.; Tramontano, A.; Niccolai, N. ProCoCoA: A quantitative approach for analyzing protein core composition. Comput. Biol. Chem., 2013, 43, 29-34.
[http://dx.doi.org/10.1016/j.compbiolchem.2012.12.007] [PMID: 23333734]
[45]
Sehnal, D. Svobodová Vařeková, R.; Berka, K.; Pravda, L.; Navrátilová, V.; Banáš, P.; Ionescu, C.M.; Otyepka, M.; Koča, J. MOLE 2.0: Advanced approach for analysis of biomacromolecular channels. J. Cheminform., 2013, 5(1), 39.
[http://dx.doi.org/10.1186/1758-2946-5-39] [PMID: 23953065]
[46]
Bernini, A.; Galderisi, S.; Spiga, O.; Amarabom, C.O.; Santucci, A. Transient pockets as mediators of gas molecules routes inside proteins: The case study of dioxygen pathway in homogentisate 1,2-dioxygenase and its implication in Alkaptonuria development. Comput. Biol. Chem., 2020, 88, 107356.
[http://dx.doi.org/10.1016/j.compbiolchem.2020.107356] [PMID: 32823072]
[47]
Cohen, J.; Olsen, K.W.; Schulten, K. Finding gas migration pathways in proteins using implicit ligand sampling. Methods Enzymol., 2008, 437, 439-457.
[http://dx.doi.org/10.1016/S0076-6879(07)37022-5] [PMID: 18433641]
[48]
Rodríguez, J.M.; Timm, D.E.; Titus, G.P.; Beltrán-Valero de Bernabé, D.; Criado, O.; Mueller, H.A.; Rodríguez de Córdoba, S.; Peñalva, M.A. Structural and functional analysis of mutations in alkaptonuria. Hum. Mol. Genet., 2000, 9(15), 2341-2350.
[http://dx.doi.org/10.1093/oxfordjournals.hmg.a018927] [PMID: 11001939]
[49]
Zatkova, A.; Sedlackova, T.; Radvansky, J.; Polakova, H.; Nemethova, M.; Aquaron, R.; Dursun, I.; Usher, J.L.; Kadasi, L. Identification of 11 Novel Homogentisate 1,2 Dioxygenase variants in Alkaptonuria patients and establishment of a Novel LOVD-Based HGD Mutation Database. JIMD Rep., 2012, 4, 55-65.
[http://dx.doi.org/10.1007/8904_2011_68] [PMID: 23430897]
[50]
Pires, D.E.V.; Ascher, D.B.; Blundell, T.L. mCSM: Predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics, 2014, 30(3), 335-342.
[http://dx.doi.org/10.1093/bioinformatics/btt691] [PMID: 24281696]
[51]
Pires, D.E.V.; Ascher, D.B.; Blundell, T.L. DUET: A server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res., 2014, 42(W1), W314-W319.
[http://dx.doi.org/10.1093/nar/gku411] [PMID: 24829462]
[52]
Ascher, D.B.; Spiga, O.; Sekelska, M.; Pires, D.E.V.; Bernini, A.; Tiezzi, M.; Kralovicova, J.; Borovska, I.; Soltysova, A.; Olsson, B.; Galderisi, S.; Cicaloni, V.; Ranganath, L.; Santucci, A.; Zatkova, A. Homogentisate 1,2-dioxygenase (HGD) gene variants, their analysis and genotype-phenotype correlations in the largest cohort of patients with AKU. Eur. J. Hum. Genet., 2019, 27(6), 888-902.
[http://dx.doi.org/10.1038/s41431-019-0354-0] [PMID: 30737480]
[53]
Spiga, O.; Cicaloni, V.; Zatkova, A.; Millucci, L.; Bernardini, G.; Bernini, A.; Marzocchi, B.; Bianchini, M.; Zugarini, A.; Rossi, A.; Zazzeri, M.; Trezza, A.; Frediani, B.; Ranganath, L.; Braconi, D.; Santucci, A. A new integrated and interactive tool applicable to inborn errors of metabolism: Application to alkaptonuria. Comput. Biol. Med., 2018, 103, 1-7.
[http://dx.doi.org/10.1016/j.compbiomed.2018.10.002] [PMID: 30316064]
[54]
Cicaloni, V; Spiga, O; Dimitri, GM; Maiocchi, R; Millucci, L Giustarini, D Interactive alkaptonuria database: Investigating clinical data to improve patient care in a rare disease. FASEB J., 2019, 33(11), 12696-12703.
[http://dx.doi.org/10.1096/fj.201901529R]
[55]
Spiga, O.; Cicaloni, V.; Fiorini, C.; Trezza, A.; Visibelli, A.; Millucci, L.; Bernardini, G.; Bernini, A.; Marzocchi, B.; Braconi, D.; Prischi, F.; Santucci, A. Machine learning application for development of a data-driven predictive model able to investigate quality of life scores in a rare disease. Orphanet J. Rare Dis., 2020, 15(1), 46.
[http://dx.doi.org/10.1186/s13023-020-1305-0] [PMID: 32050984]
[56]
Spiga, O; Cicaloni, V; Visibelli, A; Davoli, A; Paparo, MA; Orlandini, M Towards a precision medicine approach based on machine learning for tailoring medical treatment in Alkaptonuria. Int. J. Mol. Sci., 2021, 22(3), 1187.
[http://dx.doi.org/10.3390/ijms22031187]
[57]
Chen, T.; Guestrin, C. XGBoost: A scalable tree boosting system. Proceedings of the ACM SIGKDD International Conference on Knowledge Discovery and Data Mining, 2016, pp. 785-794.
[http://dx.doi.org/10.1145/2939672.2939785]
[58]
Spiga, O.; Cicaloni, V.; Dimitri, G.M.; Pettini, F.; Braconi, D.; Bernini, A.; Santucci, A. Machine learning application for patient stratification and phenotype/genotype investigation in a rare disease. Brief. Bioinform., 2021, 22(5), bbaa434.
[http://dx.doi.org/10.1093/bib/bbaa434] [PMID: 33538294]