Year-end Sale % OFF 
Abstract
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.
Highlights
Classical xanthinuria is a rare, autosomal recessive metabolic disorder characterized by impaired xanthine dehydrogenase (XDH; EC 1.17.1.4) activity that results in a lack of uric acid (UA) formation and accumulation of its precursors, xanthine (X) and hypoxanthine (HX) [1,2]
Nine Israeli families with 18 affected individuals and two sporadic cases referred from Germany are described
The experimental data for the assessment, typing and detection of xanthinuria-causing variants are provided as Supporting Information
Summary
Classical xanthinuria is a rare, autosomal recessive metabolic disorder characterized by impaired xanthine dehydrogenase (XDH; EC 1.17.1.4) activity that results in a lack of uric acid (UA) formation and accumulation of its precursors, xanthine (X) and hypoxanthine (HX) [1,2]. Classical xanthinuria occurs worldwide, yet more than two-thirds of cases are reported from the Mediterranean and Middle Eastern countries. The major clinical manifestation of xanthinuria is the formation of xanthine calculi in the urinary tract in about 40% of the affected individuals. Urolithiasis may present as hematuria, crystalluria, recurrent urinary tract infections, renal colic, acute renal failure that may lead to hydronephrosis, chronic renal failure and even death from uremia. Less frequent manifestations are myopathy, arthropathy and duodenal ulcers. Management includes high fluid intake and avoidance of purine and fructose-rich foods [1,2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
