A novel missense HGD gene mutation, K57N, in a patient with alkaptonuria

Grasko, Jonathan M.; Hooper, Amanda J.; Burnett, John R.

doi:10.1097/01268031-200941001-00177

Cited by 3 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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, 1999aF e l b o re ta l .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;Mulleretal.1999;Phornphutkul et al 2002;Porfirio et al 2000;Ramos et al 1998;Rodríguez et al 2000;T o t he ta l .2010;Uyguner et al 2003;Vilboux et al 2009;Walter et al 1999;Z a t k o v ae ta l . 2000a, b; AKUdatabase: http://www.alkaptonuria.cib.csic.es).…”

Section: The Hgd Gene Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

An update on molecular genetics of Alkaptonuria (AKU)

Zaťková

2011

J of Inher Metab Disea

View full text Add to dashboard Cite

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.

show abstract

Section: The Hgd Gene Mutationsmentioning

confidence: 99%

“…From more recent works, Grasko et al reported that the K57N missense mutation most likely exerts its effect by interfering with substrate traffic at the active site (Grasko et al 2009).…”

Section: Hgd Gene Mutation Hot Spotsmentioning

confidence: 99%

An update on molecular genetics of Alkaptonuria (AKU)

Zaťková

2011

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…In Slovakia, the country with the highest frequency of AKU, 2 recurrent variations, c.16-1G>A (INV1-1G>A) and p.G161R, were identified in more than 50% of the patients’ chromosomes, indicating that two independent founders contributed to the region’s high prevalence of AKU [Zatkova et al, 2000a; Zatkova et al, 2000b; Zatkova et al, 2003]. In addition, case reports of sequence modifications associated with AKU were described in patients of Japanese [Higashino et al, 1998], Finnish [Beltran-Valero de Bernabe et al, 1999b], Spanish [Rodriguez et al, 2000], Italian [Porfirio et al, 2000; Mannoni et al, 2004], Dominican [Goicoechea De Jorge et al, 2002], Algerian [Ladjouze-Rezig et al, 2006] and other descents [Beltran-Valero de Bernabe et al, 1998; Beltran-Valero de Bernabe et al, 1999a; Felbor et al, 1999; Phornphutkul et al, 2002; Srsen et al, 2002; Grasko et al, 2009] (Table 3). …”

Section: Review Of Previously Reported Hgd Variantsmentioning

confidence: 99%

Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria

et al. 2009

View full text Add to dashboard Cite

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene (HGD) that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense, and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8, and 13. We assessed the potential effect of all missense variations on protein function, using five bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT, and SNAP). We also analyzed the potential effect of splice-site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease.

show abstract

“…Familial segregation provided unequivocal derivation of the haplotypes present on the AKU chromosomes and clearly showed that a single haplotype, closely related to the common A haplogroup (Beltrán-Valero de Bernabé et al 1998), was harbouring the G360R mutation (Porfirio et al 2000). Subsequently, another ten compound heterozygous patients were reported to carry G360R (Grasko et al 2009;Vilboux et al 2009;Usher et al 2015). Since G360R takes place in a G run, a sequence motif known as a mutational hot spot in HGD (Beltrán-Valero de Bernabé et al 1999), referral of two large, apparently unrelated, South Tyrolean AKU families, has recently renewed our interest in the origin and spread of G360R mutation among populations of European ancestry.…”

mentioning

confidence: 99%

A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria

et al. 2016

View full text Add to dashboard Cite

We sought to establish rapid and specific genotyping methods for G360R mutation and for seven tightly linked markers in the homogentisate dioxygenase gene to address the question of whether G360R is a mutational hot spot or the result of a founder effect, as it has been repeatedly found in alkaptonuric patients from a geographic isolate in Italy.For G360R and single nucleotide polymorphism genotyping, high-resolution melting analysis was performed. Microsatellites were analysed by multiplex PCR and capillary electrophoresis. To investigate the natural history of the G360R mutation, we genotyped markers in 52 controls and in 8 unrelated patients from the UK and USA, who also segregated the G360R mutation, and calculated its age using DMLE+2.3 software.A distinct G360R-bearing haplotype was identified in all patients of Caucasian descent. Estimated mutation age was 545 generations (95% credible set, 402-854), suggesting that G360R arose in an ancestor who lived 8,000-10,000 years BC. Archaeological, historical and demographic data support that a G360R carrier has settled the remote valley where present-day population might have a heterozygote frequency of at least 6%.Given the late health-threatening complications of alkaptonuria and a cure within reach, inhabitants of this isolate would benefit from screening and genetic counselling.

show abstract

A novel missense HGD gene mutation, K57N, in a patient with alkaptonuria

Cited by 3 publications

References 0 publications

An update on molecular genetics of Alkaptonuria (AKU)

An update on molecular genetics of Alkaptonuria (AKU)

Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria

A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria

Contact Info

Product

Resources

About