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A 6-yr-old female orangutan presented with a history of dark urine that turned brown upon standing since birth. Repeated routine urinalysis and urine culture were unremarkable. Urine organic acid analysis showed elevation in homogentisic acid consistent with alkaptonuria. Sequence analysis identified a homozygous missense variant, c.1081G>A (p.Gly361Arg), of the homogentisate 1,2-dioxygenase (HGD) gene. Familial studies, molecular modeling, and comparison to human variant databases support this variant as the underlying cause of alkaptonuria in this orangutan. This is the first report of molecular confirmation of alkaptonuria in a nonhuman primate., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest in regard to publication of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In alkaptonuria, homogentisate 1,2-dioxygenase deficiency causes tissue accumulation of homogentisic acid (HGA), followed by signs and symptoms of ochronosis. These include massive urinary excretion of HGA, arthritis and joint destruction, pigmentation of cartilage and connective tissue, and cardiac valve deterioration. We describe a 46-year-old man with alkaptonuria and diabetic renal failure whose plasma HGA concentration was twice that of any other alkaptonuria patient, and whose ochronosis progressed much more rapidly than that of his two alkaptonuric siblings. After renal transplantation, the plasma HGA normalized, and the daily urinary excretion of HGA decreased by 2-3g. This case illustrates the critical role of renal tubular secretion in eliminating HGA from the body, and suggests that renal transplantation in a uremic patient not only restores HGA excretion, but may also provide homogentisate 1,2-dioxygenase activity for the metabolism of HGA.

Research on alkaptonuria (AKU; OMIM # 230500) in Slovakia started in 1968 by the Research Laboratory (later on the Institute) for Clinical Genetics at Martin. Its first stage was focused on clinical, biochemical, genetic and epidemiologic questions and on the reasons for the high prevalence of AKU in Slovakia. Based on a screening programme of now over 611,000 inhabitants (509,000 newborns) the world-wide highest incidence of AKU (1 in 19,000) was recorded, and a total of 208 patients (110 children) were registered. Extensive genealogical studies (sometimes over two centuries) resulted in the fusion of several "unrelated" nuclear families into larger pedigrees and enabled tracing most AKU ancestors to their original geographic localities, predominantly in remote mountain areas. A likely founder effect was detected among the shepherd population of the so-called Valachian colonization that resulted in a high degree of inbreeding and persisting genetic isolation. These epidemiologic data formed the basis for molecular studies in collaboration with the Würzburg group. The AKU locus was mapped to human chromosome 3q2 by orthology to the mouse locus aku. Following the cloning of the homogentisate-1,2 dioxygenase (HGD) genes from human and mouse, nine different mutations were identified in 21 AKU index patients. These include 4 missense, 2 splice-site, 2 single-base insertion and 1 deletion mutation. The most frequent mutations among the 42 AKU chromosomes of the index cases are c.648G > A (Gly161Arg; 42.9%), and c.1278insC (Pro370fs; 19.1%). To date, the genotypes of 29 patients and of 74 gene carriers from 21 families have been established. The highest prevalence and allelic heterogeneity were observed in the Kysuce district with five different mutations. Molecular epidemiology studies by haplotyping were carried out to uncover the original geographic localities of all AKU index chromosomes. This strongly suggests that several founders have contributed to the HGD gene mutation pool. While there is no straightforward explanation for the clustering of independent mutations, the genetic isolation in the past is likely to be responsible for the high prevalence of AKU in Slovakia.

Alkaptonuria (AKU; McKusick No. 203500), a rare hereditary disorder of the phenylalanine catabolism, was the first disease to be interpreted as an inborn error of metabolism (A. E. Garrod, 1902, Lancet 2: 1616-1620). AKU patients are deficient for homogentisate 1,2-dioxygenase (HGO; EC 1.13.11.5). This enzymatic deficiency causes homogentisic aciduria, ochronosis, and arthritis. Recently we cloned the human HGO gene and showed that AKU patients carry two copies of a loss-of-function HGO allele. Here we describe the complete nucleotide sequence of the human HGO gene and the identification of its promoter region. The human HGO gene spans 54,363 bp and codes for a 1715-nt-long transcript that is split into 14 exons ranging from 35 to 360 bp. The HGO introns, 605 to 17,687 bp in length, contain representatives of the major classes of repetitive elements, including several simple sequence repeats (SSR). Two of these SSRs, a (CT)n repeat in intron 4 and a (CA)n repeat in intron 13, were found to be polymorphic in a Spanish population sample. The HGO transcription start site was determined by primer extension. We report that sequences from -1074 to +89 bp (relative to the HGO transcription start site) are sufficient to promote transcription of a CAT reporter gene in human liver cells and that this fragment contains putative binding sites for liver-enriched transcription factors that might be involved in the regulation of HGO expression in liver.

Alkaptonuria is a human hereditary metabolic disease characterized by a very high urinary excretion of homogentisic acid, an intermediary product in the metabolism of tyrosine, in association with ochronosis and arthritis. This disease is due to a deficiency in the enzyme homogentisic acid oxidase and is inherited as an autosomal recessive condition. We have found a new recessive mutation (aku) in the mouse that is homologous to human alkaptonuria, during a mutagenesis program with ethylnitrosourea. Affected mice show high levels of urinary homogentisic acid without signs of ochronosis or arthritis. This mutation has been mapped to Chr 16 close to the D16Mit4 locus, in a region of synteny with human 3q.

Alkaptonuria (AKU; McKusick no. 203500) is a rare autosomal recessive disorder caused by the lack of homogentisic acid oxidase activity. Patients excrete large amounts of homogentisic acid in their urine and a black ochronotic pigment is deposited in their cartilage and collagenous tissues. Ochronosis is the predominant clinical complication of the disease leading to ochronotic arthropathy, dark urine, pigment changes of the skin, and other clinical features. A mutation causing alkaptonuria in the mouse has mapped to chromosome 16. Considering conserved synteny, we were able to map the human gene to chromosome 3q in six alkaptonuria pedigrees of Slovak origin.