A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria (original) (raw)
Related papers
Journal of Inherited Metabolic Disease, 2003
Summary: Alkaptonuria (AKU) is a rare metabolic disorder of phenylalanine catabolism that is inherited as an autosomal recessive trait. AKU is caused by loss-of-function mutations in the homogentisate 1,2-dioxygenase (HGO) gene. The deficiency of homogentisate 1,2-dioxygenase activity causes homogentisic aciduria, ochronosis and arthritis. We present the first molecular study of the HGO gene in Turkish AKU patients. Seven unrelated AKU families from different regions in Turkey were analysed. Patients in three families were homozygous for the R58fs mutation; another three families were homozygous for the R225H mutation; and one family was homozygous for the G270R mutation. Analysis of nine intragenic HGO polymorphisms showed that the R58fs, R225H and G270R Turkish AKU mutations are associated with specific HGO haplotypes. The comparison with previously reported haplotypes associated with these mutations from other populations revealed that the R225H is a recurrent mutation in Turkey, whereas G270R most likely has a Slovak origin. Most interestingly, these analyses showed that the Turkish R58fs mutation shares an HGO haplotype with the R58fs mutation found in Finland, Slovakia and India, suggesting that R58fs is an old AKU mutation that probably originated in central Asia and spread throughout Europe and Anatolia during human migrations.
American Journal of Human Genetics, 2000
Alkaptonuria (AKU) is an autosomal recessive disorder caused by the deficiency of homogentisate 1,2 dioxygenase (HGO) activity. AKU shows a very low prevalence (1:100,000-250,000) in most ethnic groups. One notable exception is in Slovakia, where the incidence of AKU rises to 1:19,000. This high incidence is difficult to explain by a classical founder effect, because as many as 10 different AKU mutations have been identified in this relatively small country. We have determined the allelic associations of 11 HGO intragenic polymorphisms for 44 AKU chromosomes from 20 Slovak pedigrees. These data were compared to the HGO haplotype data available in our laboratory for 180 AKU chromosomes from different European and non-European countries. The results show that common European AKU chromosomes have had only a marginal contribution to the Slovak AKU gene pool. Six of the ten Slovak AKU mutations, including the prevalent G152fs, G161R, G270R, and P370fs mutations, most likely originated in Slovakia. Data available for 17 Slovak AKU pedigrees indicate that most of the AKU chromosomes have their origins in a single very small region in the Carpathian mountains, in the northwestern part of the country. Since all six Slovak AKU mutations are associated with HGO mutational hot spots, we suggest that an increased mutation rate at the HGO gene is responsible for the clustering of AKU mutations in such a small geographical region.
Annals of Human Genetics, 2014
Alkaptonuria (AKU) is an autosomal recessive disorder; caused by the mutations in the homogentisate 1, 2-dioxygenase (HGD) gene located on Chromosome 3q13.33. AKU is a rare disorder with an incidence of 1: 250,000 to 1: 1,000,000, but Slovakia and the Dominican Republic have a relatively higher incidence of 1: 19,000. Our study focused on studying the frequency of AKU and identification of HGD gene mutations in nomads. HGD gene sequencing was used to identify the mutations in alkaptonurics. For the past four years, from subjects suspected to be clinically affected, we found 16 positive cases among a randomly selected cohort of 41 Indian nomads (Narikuravar) settled in the specific area of Tamil Nadu, India. HGD gene mutation analysis showed that 11 of these patients carry the same homozygous splicing mutation c.87 + 1G > A; in five cases, this mutation was found to be heterozygous, while the second AKU-causing mutation was not identified in these patients. This result indicates that the founder effect and high degree of consanguineous marriages have contributed to AKU among nomads. Eleven positive samples were homozygous for a novel mutation c.87 + 1G > A, that abolishes an intron 2 donor splice site and most likely causes skipping of exon 2. The prevalence of AKU observed earlier seems to be highly increased in people of nomadic origin.
American Journal of Human Genetics, 1999
We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1,2 dioxygenase gene (HGO). Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees. These analyses identified two novel single-nucleotide polymorphisms (INV4+31A→G and INV11+18A→G) and six novel AKU mutations (INV1-1G→A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU. Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO.
JIMD Reports, 2011
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.
R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE
Annals of Human Genetics, 2009
This 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.
JIMD reports, 2014
Alkaptonuria (AKU) is a rare autosomal recessive disorder with incidence ranging from 1:100,000 to 1:250,000. The disorder is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD), which results from defects in the HGD gene. This enzyme converts homogentisic acid to maleylacetoacetate and has a major role in the catabolism of phenylalanine and tyrosine. To elucidate the mutation spectrum of the HGD gene in patients with alkaptonuria from 42 patients attending the National Alkaptonuria Centre, 14 exons of the HGD gene and the intron-exon boundaries were analysed by PCR-based sequencing. A total of 34 sequence variants was observed, confirming the genetic heterogeneity of AKU. Of these mutations, 26 were missense substitutions and four splice site mutations. There were two deletions and one duplication giving rise to frame shifts and one substitution abolishing the translation termination codon (no stop). Nine of the mutations were previously unreported novel variants. Using computational approaches based on the 3D structure, these novel mutations are predicted to affect the activity of the protein complex through destabilisation of the individual protomer structure or through disruption of protomer-protomer interactions.