Current view on genetics of alkaptonuria


Authors: V. Bošák
Authors‘ workplace: Národný ústav reumatických chorôb, Piešťany, Slovenská republika, Fakulta zdravotníctva a sociálnej práce, Trnavská univerzita, Trnava, Slovenská republika
Published in: Čes. Revmatol., 18, 2010, No. 2, p. 92-96.
Category: Overview Reports

Overview

Alkaptonuria (AKU) is a monogenic, autosomal recessive inherited disorder that is due to a defect of the enzyme homogentisate oxidase. As a result, homogentisic acid accumulates in the organism and is excreted in urine. Its polymer, a blue-white ochronotic pigment, is deposited in cartilage and connective tissues, and causes their pigmentation (ochronosis). From a clinical perspective, the spine and large joints are most severely involved. Absence of biological activity of the hepatic enzyme homogentisate 1,2-dioxygenase (HGD) represents the biochemical basis of AKU. HGD participates in catabolism of phenylalanine and tyrosine. The HGD coding gene consists of 14 exons, 13 introns, and is located on the long arm of chromosome 3 (3q21-23). The complete length of nucleotide sequence is 54 363 bp, whereas the coding portion of the gene is only 1 715 bp long. The HGD gene is tissue specifically expressed mainly in the liver and kidneys. The defect of HGD is not caused by one mutation only, as was originally assumed. Currently, there are at least 67 known mutations, most of which are rare and specific for certain localities or families. All of them lead to a complete loss of enzymatic activity of HGD. In the Slovak population, 10 different mutations of the HGD gene were found, six of which (G270R, G161R, G152fs, P370fs, S47L, IVS5+1G→A) probably originate from a Slovak region called Kysuce. These mutations were induced by some environmental or nutritional factors. Subsequent genetic drift and isolation caused an increase in frequency of these mutations, which leaded to higher occurrence of AKU. Slovakia is characterised by the highest occurrence of AKU worldwide (incidence rate in the Slovak new-born population is 1:19 000). Molecular genetic findings in AKU have been used in DNA diagnostics, in screening for healthy carriers (heterozygotes), and could be promising towards the development of gene therapy of AKU.

Key words:
Alkaptonuria (AKU), genetics of AKU, homogentisate 1,2-dioxygenase (HGD), HGD gene, mutations


Sources

1. Rovenský J, Urbánek T. Alkaptonuria a ochronóza. In: Hrnčíř Z (eds). Klinická revmatologie. Praha: Galén; 2003. p. 509-516.

2. Garrod AE. Incidence of alkaptonuria: a study in clinical individuality. Lancet 1902; 2; 1616-20.

3. Hogben L, Worrall RL, Zieve I. The genetic basis of alkaptonuria. Proc Roy Soc Edinburg 1932; 52; 264.

4. La Du BN, Zannoni VG, Laster L, Seegmiller JE. The nature of the defect in tyrosine metabolism in alcaptonuria. J Biol Chem 1958; 230; 251-262.

5. Schmidt SR, Gehrig A, Koehler MR, Schmid M, Müller CR, Kress W. Cloning of the homogentisate-1,2-dioxygenase, the key enzyme of alkaptonuria in mouse. Mammalian Genome 1997; 8; 168-171.

6. Granadino B, Beltrán-Valero de Bernabé D, Fernández-Canón JM, Penalva MA, Rodríguez de Córdoba S. The human homogentisate 1,2-dioxygenase gene. Genomics 1997; 43; 115-122.

7. Fernandez-Canón JM, Granadino B, Beltrán-Valero de Bernabé D, Renedo M, Fernández-Ruiz E, Penalva MA, Rodríguez de Cordoba S. The molecular basis of alkaptonuria. Nat Genet 1996; 14; 19-24.

8. La Du BN. Alcaptonuria. In: Mc Graw-Hill (eds). The metabolic bases of inherited diseases. New York: 1989. p. 775-790.

9. Janocha S, Wolz W, Sršeň Š, Sršňová K, Montagutelli X, Guénet JL, Grimm T, Kress W, Müller CR. The human gene for alkaptonuria maps to chromosome 3q. Genomics 1994; 19; 5-8.

10. Beltrán-Valero de Bernabé D, Jimenez FJ, Aquaron R, Rodríguez de Cordoba S. Analysis of alkaptonuria mutations and polymorphisms reveals the the CCC sequence motif is mutational hot spot in the homogentisate 1,2 dioxygenase gene. Am J Med Genet 1999; 64; 1316-1322.

11. Porfirio B, Chiarelli I, Graziano C, Mannoni A, Morrone A, Zammarchi E, Beltrán-Valero de Bernabé D. Alkaptonuria in Italy. Polymorphic haplotype background, mutational profile and description of four novel mutations in the homogentisate 1,2-dioxygenase gene. J Med Genet 2000; 37; 309-312.

12. Zaťková A, Beltrán-Valero de Bernabe D, Poláková H, Zvarík M, Feráková E, Bošák V, et al. High frequency of alkaptonuria in Slovakia. Evidence for the appearance on mutations in HGO involving different mutational hot spots. Am J Hum Genet 2000; 67; 1333-1339.

13. Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick D L, et al. Natural history of alkaptonuria. N Engl J Med 2002; 26; 2111-2121.

14. Goicoechea de Jorge E, Lorda I, Gallardo ME, Pérez B, Pérez de Ferrán C, Mendoza H, Rodriguez de Córdoba S. Alkaptonuria in teh Dominican republic: identification of the founder AKU mutation and futher evidence of mutation hot spot in the HGO gene. J Med Gen 2002;. 39; 1-3.

15. Uyguner O, Goicoechea de Jorge E, Cefle A, Baykal T, Kayserili H, Cefle K, et al. Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58fs mutation originated from central Asia and was spread throughout Europe and Anatolia by human migrations. J Inherit Metab Dis 2003; 26; 17-23.

16. Ladjouze-Rezig A, Rodriguez de Cordoba S, Aquaron R. Ochronotic rheumatism in Algeria: clinical, radiological, biological and molecular studies-a case study of 14 patients in 11 families. Joint Bone Spine 2006; 73;. 284-292.

17. Zaťková A, Poláková H, Micutková L, Zvarík M, Bošák V, Feráková E, et al. Novel mutations in the homogentisate-1,2-dioxygenase gene identified in patients with alkaptonuria. J Med Genet 2000; 37; 539-542. .

18. Zaťková A, Beltrán-Valero de Bernabé D, Poláková H, Feráková E, Bošák V, Cisárik F, et al. Alelová heterogénnosť mutácií spôsobujúcich alkaptónúriu a možné príčiny vysokého výskytu tejto choroby na Slovensku. Lek Obz 2000; 49; 347-352.

19. Zaťková A, Poláková H, Mičutková L, Zvarík M, Feráková E, Bošák V, Kádasi L. Mutation heterogenity in Slovak alkaptonuria patients. Eur J Hum Gen 1999; 7; Suppl 1; p. 127; P-518.

20. Beighton P, Berman P, Sršeň Š. Alkaptonuria. In: McKusick’s heritable disorders of connective tissue. 5th ed. St Louis: Mosby; 1993. p. 315-334.

21. Sršeň Š. Alkaptonúria. Siťaj Š, Hyánek J (eds). Martin: Osveta; 1984. 264 p.

22. Siťaj Š. Artropatia alcaptonurica. Bratisl lek Listy 1947; 27; 1-9.

23. Siťaj Š. Alkaptonúria a ochronóza. Bratislava: SAV; 1956. 156 p.

24. Urbánek T, Siťaj Š. In: Congressus rheumatologicus čechoslovacus in thermis Piešťany 1960. Praha: SZN; 1962. p. 110-115.

25. Hüttl S, Markovič O, Siťaj Š. Der Gelenkerguß bei de ochronotischen Arthropathie. Zietschr Rheumatol 1966; 25: 169-181.

26. Kaprálik I, Sršeň Š. Analýza typu dedičnosti pri alkaptonúrii. Bratisl lek Listy 1980; 73: 459.

27. Introne WJ, Kayser MA, Gahl WA. Alkaptonuria. Available from URL: www.ncbi.nlm.nih.gov/bookshelf/alkaptonuria.

28. Grasko JM, Hooper AJ, Brown JW, McKnight CJ, Burnett JR. A novel missense HGD gene mutation K57N in a patient with alkaptonuria. Clinica Chimica Acta 2009; 403; 254-256.

29. Abdulrazzaq YM, Ibrahim A, Al-khayat AI, Nagelkerke N, Ali BR. R58fs mutation in the HGD gene in a family with alkaptonuria in the UAE. Ann Hum Genet 2009; 73; 125-130.

30. Oexle K, Engel K, Tinschert S, Haas D, Lee-Kirsch MA. Three-generational alkaptonuria in a non-consanguineous family. J Inherited Metab Dis 2008; 1-6.

31. Kobak AC, Oder G, Kobak S, Argin M, Inal V. Ochronotic arthropathy: Disappearance of alkaptonuria after liver transplantation for hepatitis B-related cirrhosis. J Clin Rheumatol 2005; 11: 323-325.

Labels
Dermatology & STDs Paediatric rheumatology Rheumatology
Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account