Novel mutations in the homogentisate- 1,2-dioxygenase gene identified in Slovak patients with alkaptonuria

Zaťková, Andrea

doi:10.1136/jmg.37.7.539

Cited by 23 publications

(29 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Thus, 7 of the 12 (58.3%) AKU mutations which most likely originated in Slovakia are associated with hypermutated sequences in the HGD while worldwide it is 40/115 (34.8%) (HGD mutation database). Therefore, it is possible that an increased mutation rate in the HGD gene in a small geographical region is responsible for the high genetic heterogeneity in Slovak AKU (Zatkova et al 2000b). However, it remains unclear which mechanism acted specifically on the HGD gene to increase its mutation rate, since similar targets are also present in other genes without evident elevated gene frequency in Slovakia (Srsen et al 2002;Zatkova et al 2000a).…”

Section: Slovak Aku Genetic Specificitiesmentioning

confidence: 99%

“…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: 99%

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

View full text Add to dashboard Cite

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.

show abstract

“…Il s'agissait de deux mutations faux-sens situées respectivement dans les exons 10 (c.855 C>T) et 12 (c.1066 T>G) qui conduisent à la substitution d'un acide aminé par un autre acide aminé : proline230serine (P230S) et valine300glycine (V300G). Depuis cette date 71 mutations différentes ont été identifiées (Tableaux 2 et 3) chez environ une centaine de patients non apparentés originaires de divers pays : Allemagne, Espagne, France, Hollande, Indes, Italie, Finlande, Japon, République dominicaine, Royaume uni, Slovaquie, Suisse, Tchéquie, Turquie et USA [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]. En dehors de la Slovaquie [43,47,48] où l'alcaptonurie existe avec une fréquence très élevée (1/25 00) [20] Récemment, la structure cristalline de la protéine enzymatique HGD a été caractérisée et a permis de comprendre l'effet de certaines mutations sur la diminution ou l'abolition de l'activité enzymatique [53].…”

Section: Mutations Du Gène De L'homogentisate 12-dioxygénase (Hgd)unclassified

“…Le phénotype est sévère car ce sujet est décédé d'une insuffisance rénale à l'âge de 61 ans. Cette mutation déjà publiée [40] a été également retrouvée chez un sujet français originaire du sud de la Pologne à l'état hétérozygote, chez un sujet américain [49], chez deux sujets tchèques et six sujets slovaques [47,48 ]. La mutation IVS1-1G>A comme les mutations R58fs, P230S et V300G sont associées avec les mêmes haplotypes et repré-sentent vraisemblablement des mutations relativement anciennes qui se sont répandues en Europe au cours des différentes migrations.…”

Section: Mutations Du Gène De L'homogentisate 12-dioxygénase (Hgd)unclassified

Le rhumatisme alcaptonurique en Algérie : étude clinique, radiologique, biologique et moléculaire : à propos de 14 cas dans 11 familles

Ladjouze-Rezig¹,

Córdoba

Aquaron³

2006

Revue du Rhumatisme

View full text Add to dashboard Cite

Novel mutations in the homogentisate- 1,2-dioxygenase gene identified in Slovak patients with alkaptonuria

Cited by 23 publications

References 21 publications

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

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

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

Le rhumatisme alcaptonurique en Algérie : étude clinique, radiologique, biologique et moléculaire : à propos de 14 cas dans 11 familles

Contact Info

Product

Resources

About