Specific knockout of kidney homogentisate 1,2-dioxygenase reveals that local metabolism of tyrosine and homogentisic acid is negligible in alkaptonuria

Rutland, DA, Norman, BP ORCID: 0000-0001-9293-4852, Hughes, JH, Wilson, PJM, Sutherland, H, Brown, RLW, Gallagher, JA, Ranganath, LR and Bou-Gharios, G (2026) Specific knockout of kidney homogentisate 1,2-dioxygenase reveals that local metabolism of tyrosine and homogentisic acid is negligible in alkaptonuria. Human Molecular Genetics, 35 (8). ISSN 0964-6906

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Abstract

Extreme metabolic phenotypes present unique opportunities to understand the participation of different organs in specific metabolite pathways. One such condition is the inherited metabolic disorder alkaptonuria (AKU), caused by mutations in the gene encoding the homogentisate 1,2-dioxygenase (HGD) enzyme. HGD is expressed in liver and kidney. In AKU, lack of functional HGD results in incomplete breakdown of the amino acid tyrosine and accumulation of homogentisic acid (HGA), the indicative metabolite in AKU. Here, we aimed to delineate the role of the kidney in production and metabolism of HGA. We generated for the first time a mouse with specific deletion of Hgd in the kidney but not in the liver, using Cre recombinase driven by Six2 (Six2^GCiP), a transcription factor expressed early in kidney development. With intact liver HGD in this mouse, plasma HGA remained equivalent to wild-type concentrations. Minimal circulating HGA combined with no apparent renal HGD activity enabled us to unmask the portion of HGA produced locally within the kidney. Urine HGA (mean ± SEM) was > 100-fold lower in kidney-specific Hgd knockout mice (717 ± 129 μmol/L) compared to AKU mice (118 364 ± 8494 μmol/L) with complete liver and kidney knockout, but higher than wild-type controls (2.3 ± 0.1 μmol/L). Profiling of tyrosine pathway metabolic enzymes showed human and mouse kidney lack detectable tyrosine aminotransferase, a key enzyme involved in tyrosine-HGA metabolism. We demonstrate both tyrosine metabolism and HGA production are minimal in kidney compared to liver. The kidney is therefore not a viable target for HGA-lowering therapies aiming to restore HGD activity.

Item Type:	Article
Uncontrolled Keywords:	Liver; Kidney; Animals; Mice, Knockout; Humans; Mice; Alkaptonuria; Disease Models, Animal; Homogentisic Acid; Tyrosine; Male; Homogentisate 1,2-Dioxygenase; alkaptonuria; kidney-specific knockout; metabolism; tyrosine; Animals; Alkaptonuria; Homogentisate 1,2-Dioxygenase; Kidney; Mice; Tyrosine; Homogentisic Acid; Mice, Knockout; Liver; Humans; Disease Models, Animal; Male; 31 Biological Sciences; 3105 Genetics; Liver Disease; Genetics; Biotechnology; Digestive Diseases; Kidney Disease; 2.1 Biological and endogenous factors; Metabolic and endocrine; Animals; Alkaptonuria; Homogentisate 1,2-Dioxygenase; Kidney; Mice; Tyrosine; Homogentisic Acid; Mice, Knockout; Liver; Humans; Disease Models, Animal; Male; 06 Biological Sciences; 11 Medical and Health Sciences; Genetics & Heredity; 3105 Genetics
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics
Divisions:	Sport and Exercise Sciences
Publisher:	Oxford University Press
Date of acceptance:	28 April 2026
Date of first compliant Open Access:	17 June 2026
Date Deposited:	17 Jun 2026 12:56
Last Modified:	17 Jun 2026 12:56
DOI or ID number:	10.1093/hmg/ddag036
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28858

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