Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene

Jorge, Elena Goicoechea de; Lorda, Isabel; Gallardo, Mercedes; Pérez, Belén López; Ferrán, C Peréz de; Mendoza, Hector; Córdoba, Santiago Rodrı́guez de

doi:10.1136/jmg.39.7.e40

Cited by 33 publications

(11 citation statements)

References 12 publications

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“…In the Dominican Republic seven of the eight AKU patients were homozygous for a c.527T→G substitution in exon 6 of the HGD gene, resulting in a missense mutation (C120W), which replaces a cysteine in position 120 with a tryptophan. The eighth patient was homozygous for the G270R (c.975G→A) missense mutation (Goicoechea De Jorge et al 2002).…”

Section: Discussionmentioning

confidence: 99%

R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE

Abdulrazzaq

Aliyu

Alkhayat

et al. 2009

Annals of Human Genetics

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SummaryThis study was conducted to determine the prevalence of alkaptonuria in the UAE population and to identify the genotype of affected individuals. In a 3 stage sampling technique 2981 pupils from Government schools in Al Ain and private schools in Dubai were selected to take part in the study, of whom 2857 provided urine samples. Urine collected was analysed for homogentisic acid by gas chromatography-mass spectrometry. Genomic DNA was isolated from the white blood cells of all family members of the affected case following standard established protocols. Specific PRC primers were designed to amplify all 14 exons of the HGD gene with the flanking intronic sequences including the splice site sequences. 2857 children returned a viable urine sample, of which one was highly positive for homogentisic acid. All 12 members of this girl's family were studied and one, a 22 year old brother, was found to excrete HGA. Another, a sister who had not provided a urine sample, was discovered by genetic testing. There were no complaints of joint pain or other symptoms in any member of this family. Parents were first cousins. We found a single nucleotide deletion c.342delA, located in exon 3, which resulted in a frameshift at amino acid position 58 (p.Arg58fs or p.R58fs). Alkaptonuria may be more common than it is thought to be with an allele prevalence estimated at 0.0107 (95% CI 0.000392 -0.03473) . The R58fs mutation is old, perhaps having occurred several thousand years ago, and has spread over a large geographical area.

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Section: Discussionmentioning

confidence: 99%

R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE

Abdulrazzaq

Aliyu

Alkhayat

et al. 2009

Annals of Human Genetics

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“…The majority of patients carry compound heterozygous variants; p.Met368Val is a common pathogenic variant in Europe except the Slovak population where mutational hot spots (e.g., c.342 + 1G>A) and a founder effect (e.g., the frequent pathogenic variant p.Gly161Arg) exist [215,225,226]. In the Dominican Republic, p.Cys120Trp is a founder variant [227]. No mutational hot spot or founder effect has been identified in the US [228].…”

Section: Geneticsmentioning

confidence: 99%

Disorders of phenylalanine and tyrosine metabolism

Alsharhan

Fıçıcıoğlu

2020

TRD

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This article provides a review of the inborn errors of phenylalanine and tyrosine metabolism including the diagnostic approach, dietary and pharmalogical management and emerging therapies. Hyperphenylalaninaemia results mainly from defects in either phenylalanine hydroxylase (PAH) (resulting in phenylketonuria (PKU)) or the production or recycling of tetrahydrobiopterin (BH 4). Untreated PKU results in irreversible neurocognitive impairment. Five inherited disorders of tyrosine metabolism are known, which include tyrosinemia type I, type II, type III, hawkinsinuria and alkaptonuria. Newborn screening for these disorders has enabled their early detection and decreased the associated morbidity and mortality.

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“…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

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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.

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Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene

Cited by 33 publications

References 12 publications

R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE

R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE

Disorders of phenylalanine and tyrosine metabolism

Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria

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