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Three‐generational alkaptonuria in a non‐consanguineous family
Author(s) -
Oexle K.,
Engel K.,
Tinschert S.,
Haas D.,
LeeKirsch M. A.
Publication year - 2008
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-008-0994-7
Subject(s) - genetics , missense mutation , alkaptonuria , biology , haplotype , homogentisic acid , pedigree chart , penetrance , proband , compound heterozygosity , consanguinity , locus (genetics) , mutation , genotype , gene , phenotype , biochemistry
Summary Objective: Alkaptonuria (AKU) is a rare inborn error of metabolism of aromatic amino acids and considered to be an autosomal recessive trait caused by mutations in the homogentisate 1,2‐dioxygenase ( HGD ) gene. A dominant pattern of inheritance has been reported but was attributed to extended consanguinity in many cases. However, we have observed a non‐consanguineous family segregating AKU in a dominant manner over three generations. Results: All affected individuals presented with typical features of AKU including darkening of the urine, ochronosis, arthropathy, and elevated urinary excretion of homogentisic acid. Sequence analysis of the HGD gene from genomic DNA of two affected individuals, uncle and niece, revealed a heterozygous missense mutation (M368V) in the uncle that was not present in his niece. Microsatellite genotyping demonstrated that both were heterozygous at the HGD locus and shared one haplotype. This haplotype did not contain a detectable HGD mutation. The haplotype was also found in a healthy son of the niece, making a dominant HGD mutation unlikely. Moreover, sequencing of cDNA from lymphoblastoid cells of the niece did not reveal an HGD mRNA with a potentially dominant‐negative effect. Conclusion: Rare causes of the uncommon AKU inheritance in this family have to be considered, ranging from the coincidence of undetectable HGD mutations to a dominant mutation of a second, hitherto unknown AKU gene.