Journal article
Homogentisate 1,2-dioxygenase (HGD) gene variants, their analysis and genotype–phenotype correlations in the largest cohort of patients with AKU
DB Ascher, O Spiga, M Sekelska, DEV Pires, A Bernini, M Tiezzi, J Kralovicova, I Borovska, A Soltysova, B Olsson, S Galderisi, V Cicaloni, L Ranganath, A Santucci, A Zatkova
European Journal of Human Genetics | NATURE PUBLISHING GROUP | Published : 2019
Open access
Abstract
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 effe..
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Awarded by European Commission
Funding Acknowledgements
We would like to thank Drs. Jozef Rovensky (Piestany, Slovakia), Kim-Hanh Le Quan Sang (Paris, France), Berardino Porfirio (Florence, Italy), Caterina Aurizi (Rome, Italy), Anastasia Skouma (Athens, Greece), Pallavi Vats (New Delhi, India), and Robert Aquaron (Marseille, France) for DNA samples of AKU patients. The European Commission Seventh Framework Program funding granted in 2012 supported the SONIA1, SONIA2, and SOFIA studies and the AKU research at the Laboratory of genetics (DevelopAKUre, project number: 304985). DBA and DEVP were funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1, APQ-00828-15). DEVP received support from the Instituto Rene Rachou (IRR/FIOCRUZ Minas) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) (409780/2016-2), Brazil. DBA was supported also by a C.J. Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476) and the Jack Brockhoff Foundation (JBF 4186, 2016). This work was partially supported by MIUR Progetto Dipartimenti di Eccellenza 2018-2022.