Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects
Autor: | Ayala Lagziel, Avraham Zeharia, Sali Usher, Mustafa Kabha, Nasser Heib, David Levartovsky, Limor Kalfon, Hava Peretz, Bettina Bork, Daniel Landau, Tzipora C Falik-Zaccai, Juergen Graessler, Florian Bittner, Vicki Zhuravel, Silke Wollers, Hannah Shalev, Hanna Mandel, Meirav Shtauber-Naamati, Steffen Rump |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
QH301-705.5 Population MOCOS Medicine (miscellaneous) Population genetics heterologous protein expression Biology XDH General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Xanthinuria Biology (General) education Gene Genetics education.field_of_study Haplotype medicine.disease xanthinuria Yemenite Jews Arabs 030104 developmental biology chemistry Cysteine desulfurase activity founder effects Molybdenum cofactor 030217 neurology & neurosurgery Founder effect |
Zdroj: | Biomedicines, Vol 9, Iss 788, p 788 (2021) Biomedicines Volume 9 Issue 7 |
ISSN: | 2227-9059 |
Popis: | Classical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the XDH (type I) or MOCOS (type II) genes. Thirteen Israeli kindred (five Jewish and eight Arab) and two isolated cases from Germany were studied between the years 1997 and 2013. Four and a branch of a fifth of these families were previously described. Here, we reported the demographic, clinical, molecular and biochemical characterizations of the remaining cases. Seven out of 20 affected individuals (35%) presented with xanthinuria-related symptoms of varied severity. Among the 10 distinct variants identified, six were novel: c.449G> T (p.(Cys150Phe)), c.1434G> A (p.(Trp478*)), c.1871C> G (p.(Ser624*)) and c.913del (p.(Leu305fs*1)) in the XDH gene and c.1046C> T (p.(Thr349Ileu)) and c.1771C> T (p.(Pro591Ser)) in the MOCOS gene. Heterologous protein expression studies revealed that the p.Cys150Phe variant within the Fe/S-I cluster-binding site impairs XDH biogenesis, the p.Thr349Ileu variant in the NifS-like domain of MOCOS affects protein stability and cysteine desulfurase activity, while the p.Pro591Ser and a previously described p.Arg776Cys variant in the C-terminal domain affect Molybdenum cofactor binding. Based on the results of haplotype analyses and historical genealogy findings, the potential dispersion of the identified variants is discussed. As far as we are aware, this is the largest cohort of xanthinuria cases described so far, substantially expanding the repertoire of pathogenic variants, characterizing structurally and functionally essential amino acid residues in the XDH and MOCOS proteins and addressing the population genetic aspects of classical xanthinuria. |
Databáze: | OpenAIRE |
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