Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.
March 1, 2015
Journal:
Eur J Hum Genet
Author:
Martina Nemethova 1, Jan Radvanszky 1, Ludevit Kadasi 1 2, David B Ascher 3, Douglas E V Pires 3, Tom L Blundell 3, Berardino Porfirio 4, Alessandro Mannoni 5, Annalisa Santucci 6, Lia Milucci 6, Silvia Sestini 7, Gianfranco Biolcati 8, Fiammetta Sorge 8, Caterina Aurizi 8, Robert Aquaron 9, Mohammed Alsbou 10, Charles Marques Lourenço 11, Kanakasabapathi Ramadevi 12, Lakshminarayan R Ranganath 13, James A Gallagher 14, Christa van Kan 15, Anthony K Hall 16, Birgitta Olsson 17, Nicolas Sireau 18, Hana Ayoob 18, Oliver G Timmis 18, Kim-Hanh Le Quan Sang 19, Federica Genovese 20, Richard Imrich 21, Jozef Rovensky 21, Rangan Srinivasaraghavan 22, Shruthi K Bharadwaj 23, Ronen Spiegel 24, Andrea Zatkova 1
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