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

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Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene
  1. E Goicoechea de Jorge1,3,
  2. I Lorda2,
  3. M E Gallardo1,
  4. B Pérez1,3,
  5. C Peréz de Ferrán4,
  6. H Mendoza4,
  7. S Rodríguez de Córdoba1,3
  1. 1Unidad de Patología Molecular, Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain
  2. 2Servicio de Genética, Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain
  3. 3Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Velázquez 144, 28006 Madrid, Spain
  4. 4Centro Nacional de Investigación en Salud Materno Infantil, Hospital de Niños Robert Reid Cabral, Abraham Lincoln 2, Santo Domingo, Dominican Republic
  1. Correspondence to:
 Dr S Rodríguez de Córdoba, Departamento de Inmunología. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Velázquez 144, 28006-Madrid, Spain;
 SRdeCordoba{at}cib.csic.es

https://doi.org/10.1136/jmg.39.7.e40

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    Alkaptonuria (AKU, MIM 203500), the first human disease to be recognised as a recessive trait and Archibald Garrod's prototype “inborn error of metabolism”,1,2 is a rare disorder of the phenylalanine and tyrosine catabolic pathway caused by the deficiency of homogentisate dioxygenase (HGO, EC 1.13.11.5) activity.3 AKU patients are homozygous, or compound heterozygous, for loss of function mutations in HGO.4 As a consequence of this defect, AKU patients cannot convert homogentisate to maleylacetoacetate, which results in homogentisic aciduria, ochronosis, and arthritis.5 AKU shows remarkable allelic heterogeneity. More than 40 different AKU mutations have been identified in a total of fewer than 100 unrelated patients from many different countries. In addition to the AKU mutations, 19 polymorphisms have been encountered within the human HGO gene (for a complete description of the HGO mutations and polymorphisms see the AKU database (http://www.cib.csic.es/~akudb/index.htm)). The analysis of the haplotype association of polymorphisms in the AKU chromosomes has been very useful for the identification of the different AKU alleles and for tracing their migration during recent human history. In this regard, it has been shown that the three most widespread AKU mutation in Europe, M368V, V300G, and P230S (representing 20%, 5%, and 5% of European AKU chromosomes, respectively) are not recurrent mutations. Instead they are probably old mutations that were introduced into Europe with the founder populations and have spread throughout western Europe with the different migrations.6 Analysis of the HGO mutations and polymorphisms has also shown that the GGG sequence motif (or its reverse complement CCC) is a mutational hot spot in the HGO gene.7

    AKU has a very low prevalence (1:100 000-250 000) in most populations. However, in certain areas, such as the Dominican Republic and Slovakia, the incidence of alkaptonuria is unusually high.8,9 In …

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