Early-onset ocular ochronosis in a girl with alkaptonuria (AKU) and a novel mutation in homogentisate 1,2-dioxygenase (HGD) (original) (raw)
Related papers
2012
Alkaptonuria (AKU) is characterised by a typical bluish-black pigmentation in connective tissue (ochronosis) that usually occurs after the age of 30 years. AKU is the first inborn error of metabolism to be understood as a recessive trait. It is caused by mutations within the gene located on the human chromosome 3q13.33, coding for the enzyme homogentisate 1,2-dioxygenase (HGD). About 650 AKU patients have been reported worldwide, and mutation analysis performed so far in about 270 cases shows a rather high heterogeneity, since 117 AKU-causing mutations have been found, also summarized in a novel HGD mutation database. Several ethnicities have been reported in which an increased incidence of AKU is observed, compared to its worldwide low prevalence (1 : 250 000 – 1 : 1 000 000). S t r e s z c z e n i e
Genetics of alkaptonuria – an overview
Acta Facultatis Pharmaceuticae Universitatis Comenianae, 2015
Alkaptonuria (AKU) is the first described inborn error of metabolism and a classical example of rare autosomal recessive disease. AKU patients carry homozygous or compound heterozygous mutations of the gene coding for enzyme homogentisate dioxygenase (HGD) involved in metabolism of tyrosine. The metabolic block in AKU causes accumulation of homogentisic acid (HGA) that, with advancing age of the patient, leads to severe and painful ochronotic arthropathy.
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.
Ochronosis – a rare metabolic disease
Romanian Journal of Rheumatology
Alkaptonuria is a rare disorder, an autosomal recessive condition with genetic determinism and hereditary transmission, having a prevalence of 1 per 1 million population in USA. The pathogenesis includes the deficiency of the homogentisate 1,2-dioxygenase (HGD) enzyme, an intermediary enzyme in phenylalanine and tyrosine catabolism. Mutations in HGD gene leads to deficient levels of functional HGD and an excess of homogentisic acid (HGA). Although HGA is rapidly excreted by the kidneys, it slowly accumulates in various tissues. Due to HGA oxidase deficiency, HGA turns into melanin-like pigment which determines: alkaptonuria, accumulation in the connective tissues, in the joints, or can make cardiovascular and genitourinary deposits. The chronic accumulation of HGA destroys the affected tissue, leading to the characteristic black-blue color and to clinical symptoms of alkaptonuria. The aim of this paper is to investigate the particularities of rheumatic manifestations in a rare metab...