Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects

Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects

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...

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Published in:Biomedicines Vol. 9; no. 7; p. 788
Main Authors: Peretz, Hava, Lagziel, Ayala, Bittner, Florian, Kabha, Mustafa, Shtauber-Naamati, Meirav, Zhuravel, Vicki, Usher, Sali, Rump, Steffen, Wollers, Silke, Bork, Bettina, Mandel, Hanna, Falik-Zaccai, Tzipora, Kalfon, Limor, Graessler, Juergen, Zeharia, Avraham, Heib, Nasser, Shalev, Hannah, Landau, Daniel, Levartovsky, David
Format: Journal Article
Language:English
Published: Basel MDPI AG 07-07-2021
MDPI
Subjects:
Amino acids
Arabs
Bioinformatics
Chromosomes
Enzymes
Genealogy
Haplotypes
Hereditary diseases
heterologous protein expression
Metabolic disorders
MOCOS
Molybdenum
Mutagenesis
Polymorphism
Population genetics
Proteins
Software
Urogenital system
Xanthinuria
XDH
Yemenite Jews
Germany
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Summary: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.
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ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines9070788