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Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy.


ABSTRACT: 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.

SUBMITTER: Nemethova M 

PROVIDER: S-EPMC4795215 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy.

Nemethova Martina M   Radvanszky Jan J   Kadasi Ludevit L   Ascher David B DB   Pires Douglas E V DE   Blundell Tom L TL   Porfirio Berardino B   Mannoni Alessandro A   Santucci Annalisa A   Milucci Lia L   Sestini Silvia S   Biolcati Gianfranco G   Sorge Fiammetta F   Aurizi Caterina C   Aquaron Robert R   Alsbou Mohammed M   Lourenço Charles Marques CM   Ramadevi Kanakasabapathi K   Ranganath Lakshminarayan R LR   Gallagher James A JA   van Kan Christa C   Hall Anthony K AK   Olsson Birgitta B   Sireau Nicolas N   Ayoob Hana H   Timmis Oliver G OG   Sang Kim-Hanh Le Quan KH   Genovese Federica F   Imrich Richard R   Rovensky Jozef J   Srinivasaraghavan Rangan R   Bharadwaj Shruthi K SK   Spiegel Ronen R   Zatkova Andrea A  

European journal of human genetics : EJHG 20150325 1


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 i  ...[more]

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