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Eur J Hum Genet. 2016 Jan;24(1):66-72. doi: 10.1038/ejhg.2015.60. Epub 2015 Mar 25.

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

Author information

1
Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia.
2
Department of Molecular Biology, Faculty of Natural Sciences, Comenius university, Bratislava, Slovakia.
3
Department of Biochemistry, Cambridge University, Cambridge, UK.
4
Medical Genetics Unit, Department of Experimental and Clinical Biomedical Sciences University of Florence, Florence, Italy.
5
Internal Medicine Division, Rheumatology Unit, Ospedali S. Maria Nuova e Palagi, Florence, Italy.
6
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy.
7
President of aimAKU, Associazione Italiana Malati di Alcaptonuria, Siena, Italy.
8
Porphyria Centre and Metabolic Rare Diseases, San Gallicano Dermatological Institute, IRCCS - IFO Rome, Rome, Italy.
9
Laboratoire de Biochimie et Biologie Moléculaire, Facultéde Médecine, Aix Marseille Université, Marseille, France.
10
Department of Pharmacology, Faculty of Medicine, Mutah University, Karak, Jordan.
11
Neurogenetics Unit, Department of Neurology School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
12
Institute of Biochemistry, Madras Medical College& Rajiv Gandhi Government General Hospital, Chennai, India.
13
Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK.
14
Department of Musculosceletal Biology, University of Liverpool, Liverpool, UK.
15
PSR group B.V., 2132 HN Hoofddorp, Netherlands.
16
Cudos B.V., 2132 HN Hoofddorp, Netherlands.
17
Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden.
18
AKU Society, Cambridge, UK.
19
Clinical Pharmacology, Department of Genetics, University Paris Descartes, IMAGINE, Necker Hospital, Paris, France.
20
Nordic Bioscience, Herlev, Denmark.
21
National Institute of Rheumatic Diseases, Piešťany, Slovakia.
22
Department of Paediatrics, JIPMER, Puducherry, India.
23
Division of Neonatology, JIPMER, Puducherry, India.
24
Emek Medical Center, Afula, Israel.

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.

PMID:
25804398
PMCID:
PMC4795215
DOI:
10.1038/ejhg.2015.60
[Indexed for MEDLINE]
Free PMC Article

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