Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ‘black bone disease’ in Italy (original) (raw)
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Translation bioinformatics, 2022
Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in the homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The aim of this study was to use some computational bioinformatics tools to predict the most pathogenic non-synonymous mutations in the HGD gene. The data was retrieved from the SNPs database of the National Center for Biotechnology Information (dbSNPs) (Oct. 2021). The primary sequence of the protein was obtained from the UniProt database (Oct. 2021). The pathogenic effect on the protein structure and function was predicted by GeneMANIA, SIFT, Provean, Polyphen-2, I-Mutant, and Project Hope software. The human HGD gene comprises a total of 423SNPs out of that 348 were found to be synonymous, 75 were missense SNPs (nsSNPs). Analysis of the nsSNPs by SIFT predicts 35 as deleterious and 40 as tolerated ones. Using Provean only 30 were deleterious while 5 SNPs were neutral. Taking the deleterious nsSNPSs to Polyphen-2, 25 nsSNPs were damaging (22 were probably damaging and 3 were possibly damaging), while 5 were benign.
A Novel Missense HGD Gene Mutation, K57N, in a Patient with Alkaptonuria
Clinica Chimica Acta, 2009
Alkaptonuria is a rare recessive disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD) caused by mutations in the HGD gene. We report the case of a 38 year-old male with known alkaptonuria who was referred to an adult metabolic clinic after initially presenting to an emergency department with renal colic and subsequently passing black ureteric calculi. He complained of severe debilitating lower back pain, worsening over the last few years. A CT scan revealed marked degenerative changes and severe narrowing of the disc spaces along the entire lumbar spine. Sequencing of the HGD gene revealed that he was a compound heterozygote for a previously described missense mutation in exon 13 (G360R) and a novel missense mutation in exon 3 (K57N). Lys(57) is conserved among species and mutation of this residue is predicted to affect HGD protein function by interfering with substrate traffic at the active site. In summary, we describe an alkaptonuric patient and report a novel missense HGD mutation, K57N.
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.