Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene

Unidad de Patología Molecular, Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain.
Journal of Medical Genetics (Impact Factor: 6.34). 08/2002; 39(7):E40.
Source: PubMed
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    • "In Slovakia, the country with the highest frequency of AKU, 2 recurrent variations, c.16-1G>A (INV1-1G>A) and p.G161R, were identified in more than 50% of the patients' chromosomes, indicating that two independent founders contributed to the region's high prevalence of AKU [Zatkova et al., 2000a; Zatkova et al., 2000b; Zatkova et al., 2003]. In addition, case reports of sequence modifications associated with AKU were described in patients of Japanese [Higashino et al., 1998], Finnish [Beltran-Valero de Bernabe et al., 1999b], Spanish [Rodriguez et al., 2000], Italian [Porfirio et al., 2000; Mannoni et al., 2004], Dominican [Goicoechea De Jorge et al., 2002], Algerian [Ladjouze- Rezig et al., 2006] and other descents [Beltran-Valero de Bernabe et al., 1998; Beltran- Valero de Bernabe et al., 1999a; Felbor et al., 1999; Phornphutkul et al., 2002; Srsen et al., 2002; Grasko et al., 2009] (Table 3). "
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    ABSTRACT: Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene (HGD) that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense, and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8, and 13. We assessed the potential effect of all missense variations on protein function, using five bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT, and SNAP). We also analyzed the potential effect of splice-site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease.
    Human Mutation 12/2009; 30(12):1611-9. DOI:10.1002/humu.21120 · 5.14 Impact Factor
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    • "The estimated prevalence of alkaptonuria in the human population is 3–5 per million (Hogben et al 1932; Knox 1958d) but that estimate may require revision. Alkaptonuria shows geographical and ethnic clustering, with conventional population-genetics explanations, in the Trencin district of Slovakia (Srsen et al 1978) and in the Dominican Republic (Goicoechea De Jorge 2002; Milch 1960). Garrod_s belief in the relatively benign nature of alkaptonuria, and of inborn errors of metabolism as a class, was supported by Osler, who saw the condition to be Fnot of much moment_ (Osler 1904). "
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    ABSTRACT: Garrod presented his concept of 'the inborn error of metabolism' in the 1908 Croonian Lectures to the Royal College of Physicians (London); he used albinism, alkaptonuria, cystinuria and pentosuria to illustrate. His lectures are perceived today as landmarks in the history of biochemistry, genetics and medicine. Garrod gave evidence for the dynamic nature of metabolism by showing involvement of normal metabolites in normal pathways made variant by Mendelian inheritance. His concepts and evidence were salient primarily among biochemists, controversial among geneticists because biometricians were dominant over Mendelists, and least salient among physicians who were not attracted to rare hereditary 'traits'. In 2008, at the centennial of Garrod's Croonian Lectures, each charter inborn error of metabolism has acquired its own genomic locus, a cloned gene, a repertoire of annotated phenotype-modifying alleles, a gene product with known structure and function, and altered function in the Mendelian variant.
    Journal of Inherited Metabolic Disease 11/2008; 31(5):580-98. DOI:10.1007/s10545-008-0984-9 · 3.37 Impact Factor
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    ABSTRACT: Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of alkaptonuria. We evaluated 58 patients with alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively. Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. Twenty-three new HGO mutations were identified. In a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone (7 days at a dose of 0.7 mg per day and 3 days at 2.8 mg per day). In a 59-year-old woman, urinary HGA fell from 6.4 g to 1.7 g per day after nine days of treatment with nitisinone (0.7 mg per day). Plasma tyrosine levels in these patients rose from approximately 1.1 mg per deciliter (60 micromol per liter) in both to approximately 12.8 mg per deciliter (700 micromol per liter) and 23.6 mg per deciliter (1300 micromol per liter), respectively, with no clinical signs or symptoms. The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation.
    New England Journal of Medicine 01/2003; 347(26):2111-21. DOI:10.1056/NEJMoa021736 · 55.87 Impact Factor
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