Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients

American Journal of Human Genetics
D Beltrán-Valero de BernabéS R de Córdoba

Abstract

Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively freq...Continue Reading

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Citations

Dec 20, 2008·Journal of Inherited Metabolic Disease·K OexleM A Lee-Kirsch
Jul 2, 2011·Journal of Inherited Metabolic Disease·Andrea Zatkova
Sep 20, 2011·Journal of Inherited Metabolic Disease·Robert Raphael Aquaron
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Jun 13, 2002·Acta Ophthalmologica Scandinavica·Sevin Söker CakmakSedat Ava
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Jun 30, 2009·American Journal of Human Genetics·Michael J Dougherty
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Jan 14, 2020·Journal of Pediatric Endocrinology & Metabolism : JPEM·Alper Ilker AkbabaAli Dursun
Mar 23, 2021·European Journal of Medical Genetics·Pelin Teke KisaNur Arslan

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