Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database

Abstract

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.

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

“…13 Although a clear founder effect was observed in the Dominican republic, 11 in Slovakia, already 13 different HGD variants affecting function are reported in 121 AKU chromosomes, though most of the patients in this country come from a previously genetically isolated region. [7][8][9][32][33][34][35] The most frequent variant found in Slovakia is p.Gly161Arg, present in 45% of all AKU alleles (HGD mutation database).…”

“…8 Variants were reported according to the Human Genome Variation Society (HGVS) nomenclature additions 16 and their description is based on coding DNA Reference Sequence NM_000187.3 (genomic reference sequence NG_011957.1). Exons are numbered like in the study by Granadino et al 4 Variants and other patient data were deposited in the HGD gene mutation database (http://hgddatabase.cvtisr.sk/), 8 using a specific family/allele code. Variant nomenclature was verified using MUTALYSER Name Checker (https://www.mutalyzer.nl/).…”

“…cvtisr.sk/). [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.…”

Meta-analysis of differentially expressed genes in ankylosing spondylitis

“…The downregulated gene with the largest ES (1.2299) was mitochondrial ribosomal protein S11 (MRPS11), which plays a role in protein synthesis within the mitochondrion (Emdadul Haque et al, 2008). The downregulated gene with the lowest P value (0.005673) was homogentisate 1,2-dioxygenase (HGD), which is involved in the catabolism of the amino acids tyrosine and phenylalanine (Zatkova et al, 2012). HGD deficiency is associated with bone deformity in AS (Balaban et al, 2006).…”

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

“…At this writing, 174 unique HGD sequence variants found in 398 individuals carrying a total of 751 variants are reported in the database. In particular, the missense mutation c.1078G>C; p.Gly360Arg (henceforth, G360R) in exon 13 has been detected 13 times in patients from Italy, Australia, the UK, France and the USA (Zatkova et al 2012). G360R was originally described by Porfirio et al (2000) who found two independent G360R-bearing AKU chromosomes in two patients from different ends of the Italian peninsula; one patient was a compound heterozygote from Calabria, Southern Italy, whereas the other was the affected son of a consanguineous marriage from South Tyrol, a German-speaking region on the Austrian border.…”