Expression of tyrosine pathway enzymes in mice demonstrates that homogentisate 1,2-dioxygenase deficiency in the liver is responsible for homogentisic acid-derived ochronotic pigmentation.


Wilson, Peter JM, Ranganath, Lakshminarayan R, Bou-Gharios, George, Gallagher, James A ORCID: 0000-0002-0852-279X and Hughes, Juliette H ORCID: 0000-0001-6155-4136 (2021) Expression of tyrosine pathway enzymes in mice demonstrates that homogentisate 1,2-dioxygenase deficiency in the liver is responsible for homogentisic acid-derived ochronotic pigmentation. JIMD reports, 58 (1). pp. 52-60.

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Abstract

Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase (HGD) deficiency. This study aimed to determine if HGD and other enzymes related to tyrosine metabolism are associated with the location of ochronotic pigment. Liver, kidney, skin, bone, brain, eyes, spleen, intestine, lung, heart, cartilage, and muscle were harvested from 6 AKU BALB/c <i>Hgd</i> <sup><i>-/-</i></sup> (3 females, 3 males) and 4 male C57BL/6 wild type (WT) mice. <i>Hgd</i>, 4-hydroxyphenylpyruvate dioxygenase (<i>4</i>-<i>Hppd</i>), tyrosine hydroxylase (<i>Th</i>), and tyrosinase (<i>Tyr</i>) mRNA expression was investigated using qPCR. Adrenal gland and gonads from AKU <i>Hgd tm1a -/-</i> mice were <i>LacZ</i> stained, followed by qPCR analysis of <i>Hgd</i> mRNA. The liver had the highest expression of <i>Hgd</i>, followed by the kidney, with none detected in cartilage or brain. Low-level <i>Hgd</i> expression was observed within developing male germ cells within the testis and epididymis in <i>Hgd tm1a -/-</i>. 4-<i>Hppd</i> was most abundant in liver, with smaller amounts in kidney and low-level expression in other tissues. <i>Th</i> was expressed mainly in brain and <i>Tyr</i> was found primarily in the eyes. The tissue distribution of both <i>Hgd</i> and 4-<i>Hppd</i> suggest that ochronotic pigment in AKU mice is a consequence of enzymes within the liver, and not from enzymatic activity within ochronotic tissues. Excessive accumulation of HGA as ochronotic pigment in joints and other connective tissues originates from the circulation and therefore the extracellular fluid. The tissue distribution of both <i>Th</i> and <i>Tyr</i> suggests that these enzymes are not involved in the formation of HGA-derived ochronotic pigment.

Item Type: Article
Uncontrolled Keywords: 4‐hydroxyphenylpyruvate dioxygenase, LacZ reporter, alkaptonuria, homogentisate 1,2‐dioxygenase, tyrosinase, tyrosine hydroxylase
Depositing User: Symplectic Admin
Date Deposited: 07 Dec 2020 08:30
Last Modified: 18 Jan 2023 23:19
DOI: 10.1002/jmd2.12184
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3109389
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