Alkaptonuria in Russia: mutational spectrum and novel variants

Alkaptonuria is a rare genetic disease caused by mutations in HGD gene. Here we report the results of genetic and biochemical analysis of 49 Russian patients with alkaptonuria. One of the common variants c.481G > A; p.(Gly161Arg) comprising 72.4% of identified alleles was found in 45 of 49 patien...

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Published in:European journal of medical genetics 2021-04, Vol.64 (4), p.104165-104165, Article 104165
Main Authors: Bychkov, Igor, Kamenets, Elena, Kurkina, Marina, Rychkov, Georgiy, Ilyushkina, Alexandra, Filatova, Aleksandra, Guseva, Darya, Baydakova, Galina, Nekrasov, Andrey, Cheblokov, Aleksandr, Skoblov, Mikhail, Zakharova, Ekaterina
Format: Article
Language:English
Subjects:
Cryptic splicing site
HGD
Homogentisate 1,2-dioxygenase
Homogentisic acid
Minigene assay
Molecular dynamics
mRNA analysis
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Summary:Alkaptonuria is a rare genetic disease caused by mutations in HGD gene. Here we report the results of genetic and biochemical analysis of 49 Russian patients with alkaptonuria. One of the common variants c.481G > A; p.(Gly161Arg) comprising 72.4% of identified alleles was found in 45 of 49 patients in our cohort, which is probably the highest frequency of this variant worldwide. 9 novel variants were found: 6 missense, 2 splicing and 1 loss of start-codon. For missense variants we performed bioinformatic analysis, protein 3D-modeling and molecular dynamics simulations, which strongly suggest their pathogenic effect. For the rare synonymous variant c.753C > T; p.(Gly251Gly), which was found in 3 cases and predicted to activate cryptic splice site, we performed the detailed functional analysis on patient's cDNA and minigene assay and confirmed its pathogenicity.
ISSN:1769-7212
1878-0849
DOI:10.1016/j.ejmg.2021.104165