Alkaptonuria in an orangutan (<i>Pongo pygmaeus</i>)

Keeling, Michale E.; McClure, Harold M.; Kibler, Robert F.

doi:10.1002/ajpa.1330380245

Cited by 8 publications

(4 citation statements)

References 6 publications

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“…Other models of ochronosis have been reported, but are generally not useful or viable for experimental studies 13,14 . Following anecdotal descriptions of ochronosis in Hgd +/− Fah −/− mice withdrawn from NTBC, we undertook both a macro- and microscopic study of their tissues.…”

Section: Introductionmentioning

confidence: 99%

Ochronosis in a murine model of alkaptonuria is synonymous to that in the human condition

Taylor

Preston

Paulk

et al. 2012

Osteoarthritis and Cartilage

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Objective Alkaptonuria (AKU) is a rare genetic disease which results in severe early onset osteoarthropathy. It has recently been shown that the subchondral interface is of key significance in disease pathogenesis. Human surgical tissues are often beyond this initial stage and there is no published murine model of pathogenesis, to study the natural history of the disease. The murine genotype exists but it has been reported not to demonstrate ochronotic osteoarthropathy consistent with the human disease. Recent anecdotal evidence of macroscopic renal ochronosis in a mouse model of tyrosinaemia led us to perform histological analysis of tissues of these mice that are known to be affected in human AKU. Design The homogentisate 1,2-dioxygenase Hgd+/−Fah−/− mouse can model either hereditary tyrosinaemia type I (HT1) or AKU depending on selection conditions. Mice having undergone Hgd reversion were sacrificed at various time points, and their tissues taken for histological analysis. Sections were stained with haematoxylin eosin (H&E) and Schmorl’s reagent. Results Early time point observations at 8 months showed no sign of macroscopic ochronosis of tissues. Macroscopic examination at 13 months revealed ochronosis of the kidneys. Microscopic analysis of the kidneys revealed large pigmented nodules displaying distinct ochre colouration. Close microscopic examination of the distal femur and proximal fibula at the subchondral junctions revealed the presence of numerous pigmented chondrocytes. Conclusions Here we present the first data showing ochronosis of tissues in a murine model of AKU. These preliminary histological observations provide a stimulus for further studies into the natural history of the disease to provide a greater understanding of this class of arthropathy.

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Section: Introductionmentioning

confidence: 99%

Ochronosis in a murine model of alkaptonuria is synonymous to that in the human condition

Taylor

Preston

Paulk

et al. 2012

Osteoarthritis and Cartilage

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“…All the reports identify the appearance of dark urine but rarely identify ochronosis or joint involvement. [52][53][54][55][56] Early attempts to study AKU in animal models were undertaken by intraperitoneal or intravenous and intra-articular injection of HGA into rabbits. 57 The study demonstrated the damaging effects of HGA.…”

Section: Models Of Akumentioning

confidence: 99%

“…60,61 Other animal models have produced similar reports, although arguably not as reliable. 54 Contrary to the above reports, Taylor et al produced the first data of tissue ochronosis in a murine model. The data from this study demonstrated ochronosis in tissues and joints of mice with the AKU genotype, similar to the presentation seen in humans.…”

Section: Models Of Akumentioning

confidence: 99%

Alkaptonuria

2013

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“…AKU has also been described in a rabbit [Lewis, 1926] and in different primates, chimpanzee [Watkins et al, 1970] and orangutan [Keeling et al, 1973]. …”

Section: Introductionmentioning

confidence: 99%

Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria

et al. 2009

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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.

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Alkaptonuria in an orangutan (Pongo pygmaeus)

Cited by 8 publications

References 6 publications

Ochronosis in a murine model of alkaptonuria is synonymous to that in the human condition

Ochronosis in a murine model of alkaptonuria is synonymous to that in the human condition

Alkaptonuria

Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria

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