Mutation spectrum of homogentisic acid oxidase (<i>HGD</i>) in alkaptonuria

Vilboux, Thierry; Kayser, Michael A.; Introne, Wendy J.; Suwannarat, Pim; Bernardini, Isa; Fischer, Roxanne; O’Brien, Kevin; Kleta, Robert; Huizing, Marjan; Gahl, William A.

doi:10.1002/humu.21120

Cited by 76 publications

(77 citation statements)

References 56 publications

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“…There is no room in this region to accommodate a significant change, and so, this mutation would be very disruptive to hexamer formation, as it would interfere and block two separate protomer-protomer interactions. Interestingly, polymorphism c.650-86A4G was described by Vilboux et al 19 Unfortunately, the cDNA of the patient is not available for analysis in order to confirm the splicing effect. We plan to perform MLPA analysis in this patient, in order to test for a presence of possible larger deletions.…”

Section: Discussionmentioning

confidence: 99%

“…These tools were selected as they use information on 3D structure of the protein and may be more reliable for HGD variants, as was shown before. 19 We also used mCSM 20 and DUET 21 in order to predict the effects of variants on a structural basis. These latter approaches are novel machine-learning algorithms that use the three dimensional structure in order to predict quantitatively the effects of point variants on protein stability and proteinprotein and protein-nucleic acid affinities.…”

Section: Variant Verificationmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Variant Verificationmentioning

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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“…Although no data are available on sub-Saharan populations (http://hgddatabase. cvtisr.sk/), lack of G360R detection among African-American AKU patients would seem to confirm indirectly that this mutation is rare (if not absent) in Africa (Phornphutkul et al 2002;Vilboux et al 2009).…”

Section: Discussionmentioning

confidence: 94%

“…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: 95%

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

et al. 2016

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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.

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“…12 Although difficult to perform with such a rare condition, there is also no genotype-phenotype correlation; all mutations lead to the development of ochronosis. 13 Research is still ongoing to fully understand the mechanism of disease progression; literature suggests the reporting of new cases has increased due to a raised profile of features associated with the disease. 10 However, even with the increase in reporting alkaptonuria (aKU) is a rare disorder of autosomal recessive inheritance.…”

Section: Epidemiologymentioning

confidence: 99%