Allelic heterogeneity of alkaptonuria in Central Europe

Müller, C. R.; Fregin, Andreas; Srsen, S; Srsnová, K; Halliger-Keller, B.; Felbor, Ute; Seemanová, E; Kreß, Wolfram

doi:10.1038/sj.ejhg.5200343

Cited by 30 publications

(28 citation statements)

References 14 publications

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“…This increase is especially noticeable in Slovakia where 208 patients have been registered, including 110 children (Srsen et al 2002). Ten different HGD mutations have currently been reported in Slovakia (Gehrig et al 1997;Muller et al 1999;Zatkova et al 2000b;Zatkova et al 2003;Zatkova et al 2000c), and therefore it is difficult to explain the increased incidence of AKU in this relatively small country by a classical founder effect.…”

Section: Introductionmentioning

confidence: 89%

Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database

et al. 2011

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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 genotypephenotype correlations and also for future clinical trials.

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Section: Introductionmentioning

confidence: 89%

Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database

et al. 2011

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“…Including present data, there are 34 Italian families reported in the HGD mutation database and previously published. 7,[27][28][29]32,33 In this rather small group, 26 different AKU-causing mutations were described, indicating high heterogeneity. Moreover, 12 of these mutations seem to be specific for Italy.…”

Section: Discussionmentioning

confidence: 99%

“…13 Although a clear founder effect was observed in the Dominican republic, 11 in Slovakia, already 13 different HGD variants affecting function are reported in 121 AKU chromosomes, though most of the patients in this country come from a previously genetically isolated region. [7][8][9][32][33][34][35] The most frequent variant found in Slovakia is p.Gly161Arg, present in 45% of all AKU alleles (HGD mutation database).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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.557T4A), Slovakia (c.500C4T) and France (c.440T4C), three in patients from India (c.469+6T4C, c.650-85A4G, c.158G4A), and six in patients from Italy (c.742A4G, c.614G4A, c.1057A4C, c.752G4A, c.119A4C, c.926G4T). 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.

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“…Mutation screening within the HGD gene has been performed in several countries, and until recently 96 mutations and 33 HGD polymorphisms had been encountered, including three variable dinucleotide repeats, HGO1-3 (Aquaron et al 2009;Beltrán-Valero de Bernabé et al 1998, 1999aFelbor et al 1999;Fernández-Cañón et al 1996;Gehrig et al 1997;Goicoechea De Jorge et al 2002;Grasko et al 2009;Higashino et al 1998;Ladjouze-Rezig et al 2006;Mannoni et al 2004;Muller et al 1999;Phornphutkul et al 2002;Porfirio et al 2000;Ramos et al 1998;Rodríguez et al 2000;Toth et al 2010;Uyguner et al 2003;Vilboux et al 2009;Walter et al 1999;Zatkova et al 2000a, b; AKUdatabase: http://www.alkaptonuria.cib.csic.es). In addition, recently we described 11 novel HGD mutations discovered during the analysis of 13 index AKU patients from Slovak families and a further 15 index cases from different countries sent to our laboratory for mutation analysis (Zatkova et al 2011).…”

Section: Mapping and Cloning Of The Human Aku Genementioning

confidence: 98%

An update on molecular genetics of Alkaptonuria (AKU)

Zaťková

2011

J of Inher Metab Disea

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Alkaptonuria (AKU) is an autosomal recessive disorder caused by a deficiency of homogentisate 1,2 dioxygenase (HGD) and characterized by homogentisic aciduria, ochronosis, and ochronotic arthritis. The defect is caused by mutations in the HGD gene, which maps to the human chromosome 3q21-q23. AKU shows a very low prevalence (1:100,000-250,000) in most ethnic groups, but there are countries such as Slovakia and the Dominican Republic in which the incidence of this disorder rises to as much as 1:19,000. In this work, we summarize the genetic aspects of AKU in general and the distribution of all known disease-causing mutations reported so far. We focus on special features of AKU in Slovakia, which is one of the countries with an increased incidence of this rare metabolic disorder.

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Allelic heterogeneity of alkaptonuria in Central Europe

Cited by 30 publications

References 14 publications

Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database

Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database

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

An update on molecular genetics of Alkaptonuria (AKU)

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