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Eur J Hum Genet. 2019 Jun;27(6):888-902. doi: 10.1038/s41431-019-0354-0. Epub 2019 Feb 8.

Homogentisate 1,2-dioxygenase (HGD) gene variants, their analysis and genotype-phenotype correlations in the largest cohort of patients with AKU.

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Department of Biochemistry and Molecular Biology, Bio21 Institute Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
Department of Biochemistry, Cambridge University, Cambridge, UK.
Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-22, University of Siena, Siena, Italy.
Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
Center of Biosciences, Institute of Molecular Physiology and Genetics, Slovak Academy of Science, Bratislava, Slovakia.
Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia.
Clinical Development, Swedish Orphan Biovitrum AB, Stockholm, Sweden.
Toscana life Sciences (TLS), Siena, Italy.
Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK.
Centro Interdipartimentale per lo Studio Biochimico delle Patologie Osteoarticolari, Università di Siena, Siena, Italy.
Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.


Alkaptonuria (AKU) is a rare metabolic disorder caused by a deficient enzyme in the tyrosine degradation pathway, homogentisate 1,2-dioxygenase (HGD). In 172 AKU patients from 39 countries, we identified 28 novel variants of the HGD gene, which include three larger genomic deletions within this gene discovered via self-designed multiplex ligation-dependent probe amplification (MLPA) probes. In addition, using a reporter minigene assay, we provide evidence that three of eight tested variants potentially affecting splicing cause exon skipping or cryptic splice-site activation. Extensive bioinformatics analysis of novel missense variants, and of the entire HGD monomer, confirmed mCSM as an effective computational tool for evaluating possible enzyme inactivation mechanisms. For the first time for AKU, a genotype-phenotype correlation study was performed for the three most frequent HGD variants identified in the Suitability Of Nitisinone in Alkaptonuria 2 (SONIA2) study. We found a small but statistically significant difference in urinary homogentisic acid (HGA) excretion, corrected for dietary protein intake, between variants leading to 1% or >30% residual HGD activity. There was, interestingly, no difference in serum levels or absolute urinary excretion of HGA, or clinical symptoms, indicating that protein intake is more important than differences in HGD variants for the amounts of HGA that accumulate in the body of AKU patients.


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