Genetics of alkaptonuria – an overview (original) (raw)
2015, Acta Facultatis Pharmaceuticae Universitatis Comenianae
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.
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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
Alkaptonuria, a Rare Genetic Disorder and its Molecular Basis
Alkaptonuria (AKU) involves a one of a noticeable place in the historical background of human hereditary qualities since it was the principal infection to be translated as a Mendelian latent attribute by Garrod in 1902. Alkaptonuria is an uncommon metabolic issue coming about because of loss of homogentisate 1, 2 dioxygenase (HGO) movement. Mutations become the cause of this leads which may be due to loss-of-function mutation and missense mutation. Influenced people gather expansive amounts of homogentisic corrosive, a mediator result of the catabolism of tyrosine and phenylalanine, which obscures the urine and stores in connective tissues bringing on an incapacitating joint inflammation. Dietary confinement of tyrosine and phenylalanine lead to a decrease in the generation of HGA, however, a serious limitation of the mentioned amino acids is harmful in the long run and might be perilous.
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.
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