Abstract
Enzymatic loss in alkaptonuria (AKU), an autosomal recessive disorder, is caused by mutations in the homogentisate 1,2 dioxygenase (HGD) gene, which decrease or completely inactivate the function of the HGD protein to metabolize homogentisic acid (HGA). AKU shows a very low prevalence (1:100,000–250,000) in most ethnic groups, but there are countries with much higher incidence, such as Slovakia and the Dominican Republic. In this work, we report 11 novel HGD mutations identified during analysis of 36 AKU patients and 41 family members from 27 families originating from 9 different countries, mainly from Slovakia and France. In Slovak patients, we identified two additional mutations, thus a total number of HGD mutations identified in this small country is 12. In order to record AKU-causing mutations and variants of the HGD gene, we have created a HGD mutation database that is open for future submissions and is available online (http://hgddatabase.cvtisr.sk/). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from the original AKU database (http://www.alkaptonuria.cib.csic.es) and also all so far reported variants and AKU patients. Where available, HGD-haplotypes associated with the mutations are also presented. Currently, this database contains 148 unique variants, of which 115 are reported pathogenic mutations. It provides a valuable tool for information exchange in AKU research and care fields and certainly presents a useful data source for genotype–phenotype correlations and also for future clinical trials.
Competing interests: None declared.
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Acknowledgment
We thank Dr. Klara Srsnova for help in summarizing information concerning Slovak AKU patients. We also thank Prof. Santiago Rodríguez de Córdoba for his initial help, and advice, and especially for making available original data from the AKU database. We highly appreciate Jacoppo Celli (Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands) and Jana Pigosova (Slovak Centre of Scientific and Technical Information (SCSTI), Bratislava, Slovakia) for their expertise in database construction and installation.
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Communicated by: James A Gallagher.
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Details of the Contributions of Individual Authors
AZ performed majority of work, including the analysis of patients, haplotype constructions, database construction and writing the manuscript. TS, MN, and HP contributed to the mutation analysis, JR contributed to the CA-repeat analysis for haplotypes, RA, ID provided patients DNA. JLU performed mutation analysis in patients from United Kingdom. All authors approved the content of the final version of the manuscript.
Funding
This research was funded by IMPG SAS and FNS UK Bratislava, Slovakia and the project “Infrastructure for research and development- data center for research and development” with the financial support of European fund for regional development (project code: 26210120001, 26230120001).
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No special ethic approval was needed. All patients signed informed consent for DNA analysis prior to a peripheral blood sample was taken from them.
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Zatkova, A. et al. (2012). Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database. In: JIMD Reports - Case and Research Reports, 2012/1. JIMD Reports, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_68
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DOI: https://doi.org/10.1007/8904_2011_68
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