Mutation Screening of the<i>HGD</i>Gene Identifies a Novel Alkaptonuria Mutation with Significant Founder Effect and High Prevalence

Sakthivel, S.; Zaťková, Andrea; Nemethova, Martina; Surovy, Milan; Kádaši, Ľudevít; Saravanan, Madurai P.

doi:10.1111/ahg.12055

Cited by 24 publications

(14 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[6][7][8] Some of the reported HGD variants are spread throughout the world, such as c.175delA (p.(Ser59Alafs*52)), one of the first identified AKU mutations, c.899T4G (p.(Val300Gly)). 7 On the other hand, there are variants rather specific for some countries or regions; for example, c.342+1G4A (ivs5+1G4A) for Slovakia and the Czech Republic, 9 c.87+1G4A (ivs2+1G4A) for the gypsy community Narikuravar in India 10 or c.360T4G (p.(Cys120Trp)) for the Dominican Republic. 11 So far, about 950 AKU patients have been reported in 61 countries worldwide (AKU Society, www.akusociety.org).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

Self Cite

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: Introductionmentioning

confidence: 99%

“…12 This country and the Dominican Republic exhibit prevalence of AKU of up to 1:19 000. 13,14 Recently, a high number of AKU cases were also found in Jordan 15 and India, 10 indicating that the overall prevalence of this disease in some countries might be underestimated.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…All variants are summarized in the HGD mutation database (13-15). p.R58fs is one of the first identified AKU mutations (16)(17)(18)(19). At the same time, there are variants rather specific to some countries or regions.…”

Section: Discussionmentioning

confidence: 99%

“…Slovakia and the Dominican Republic exhibit a prevalence of AKU up to 1:19 000 (21,22). Recently, a high number of AKU cases were also found in Jordan (23) and India (18). Nemethova et al (24) reported 99 AKU patients with 12 novel mutations from Italy.…”

Section: Discussionmentioning

confidence: 99%

Demographic, Phenotypic and Genotypic Features of Alkaptonuria Patients: A Single Centre Experience

Kılavuz¹,

Bulut²,

Kör³

et al. 2018

jpr

View full text Add to dashboard Cite

Alkaptonuria (AKU) is an autosomal recessively inherited disease caused by a deficiency of homogentisate 1,2-dioxygenase. This enzyme converts homogentisic acid (HGA) into maleylacetoacetic acid in the tyrosine degradation pathway. The presence of HGA in urine, ochronosis (bluish-black pigmentation in connective tissues) and arthritis of the spine and the other large joints are the three major features of AKU. Nitisinone and a tyrosinerestricted diet are the treatment options. In this study, we evaluated the demographic and clinical characteristics and also the mutations of our AKU patients. Materials and Methods: This retrospective single centre study included 36 patients who were diagnosed as AKU between the years of 2002 and

show abstract

“…AKU is very rare in most ethnic groups (one in 250,000-1,000,000), but in some countries, such as Slovakia and recently Jordan and India, it exhibits increased prevalence. [13][14][15][16] Thanks to the work of patient organizations, effectively coordinated by the AKU Society, many new patients have been discovered. A new overview map has recently been created that reports 1,233 AKU patients worldwide ( Figure 2, courtesy of AKU Society, Ciaran Scott).…”

Section: Genetics Of Aku and The Hgd Mutation Databasementioning

confidence: 99%

<p>Alkaptonuria: Current Perspectives</p>

Zaťková

Ranganath

Kádaši

2020

TACG

Self Cite

View full text Add to dashboard Cite

The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate dioxygenase (HGD), the enzyme involved in metabolism of tyrosine, and is characterized by the presence of dark ochronotic pigment in the connective tissue that is formed, due to high levels of circulating homogentisic acid. Almost 120 years ago, Sir Archibald Garrod used AKU to illustrate the concept of Mendelian inheritance in man. In January 2019, the phase III clinical study SONIA 2 was completed, which tested the effectiveness and safety of nitisinone in the treatment of AKU. Results were positive, and they will serve as the basis for the application for registration of nitisinone for treatment of AKU at the European Medicines Agency. Therefore, AKU might become a rare disease for which a cure will be found by 2020. We understand the natural history of the disease and the process of ochronosis much more, but at the same time there are still unanswered questions. One of them is the issue of the factors influencing the varying severity of the disease, since our recent genotype-phenotype study did not show that differences in residual homogentisic acid activity caused by the different mutations was responsible. Although nitisinone has proved to arrest the process of ochronosis, it has some unwanted effects and does not cure the disease completely. As such, enzyme replacement or gene therapy might become a new focus of AKU research, for which a novel suitable mouse model of AKU is available already. We believe that the story of AKU is also a story of effective collaboration between scientists and patients that might serve as an example for other rare diseases.

show abstract

Mutation Screening of theHGDGene Identifies a Novel Alkaptonuria Mutation with Significant Founder Effect and High Prevalence

Cited by 24 publications

References 36 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

Demographic, Phenotypic and Genotypic Features of Alkaptonuria Patients: A Single Centre Experience

<p>Alkaptonuria: Current Perspectives</p>

Contact Info

Product

Resources

About