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 <i>XDH</i> (type I) or <i>MOCOS</i> (type II) genes. Thirteen Israeli kindred (five Jewish and eight Arab) and two isolated cases from Germany were studied between the years 1997...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/9/7/788 |
| _version_ | 1797527585033289728 |
|---|---|
| author | Hava Peretz Ayala Lagziel Florian Bittner Mustafa Kabha Meirav Shtauber-Naamati Vicki Zhuravel Sali Usher Steffen Rump Silke Wollers Bettina Bork Hanna Mandel Tzipora Falik-Zaccai Limor Kalfon Juergen Graessler Avraham Zeharia Nasser Heib Hannah Shalev Daniel Landau David Levartovsky |
| author_facet | Hava Peretz Ayala Lagziel Florian Bittner Mustafa Kabha Meirav Shtauber-Naamati Vicki Zhuravel Sali Usher Steffen Rump Silke Wollers Bettina Bork Hanna Mandel Tzipora Falik-Zaccai Limor Kalfon Juergen Graessler Avraham Zeharia Nasser Heib Hannah Shalev Daniel Landau David Levartovsky |
| author_sort | Hava Peretz |
| collection | DOAJ |
| description | Classical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the <i>XDH</i> (type I) or <i>MOCOS</i> (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 <i>XDH</i> gene and c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)) in the <i>MOCOS</i> 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. |
| first_indexed | 2024-03-10T09:44:50Z |
| format | Article |
| id | doaj.art-39f61b1380a64273a9863f181879c35b |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T09:44:50Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-39f61b1380a64273a9863f181879c35b2023-11-22T03:17:01ZengMDPI AGBiomedicines2227-90592021-07-019778810.3390/biomedicines9070788Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics AspectsHava Peretz0Ayala Lagziel1Florian Bittner2Mustafa Kabha3Meirav Shtauber-Naamati4Vicki Zhuravel5Sali Usher6Steffen Rump7Silke Wollers8Bettina Bork9Hanna Mandel10Tzipora Falik-Zaccai11Limor Kalfon12Juergen Graessler13Avraham Zeharia14Nasser Heib15Hannah Shalev16Daniel Landau17David Levartovsky18Sourasky Medical Center, Clinical Biochemistry Laboratory, Tel Aviv 6423906, IsraelSourasky Medical Center, Clinical Biochemistry Laboratory, Tel Aviv 6423906, IsraelDepartment of Plant Biology, Braunschweig University of Technology, 38114 Braunschweig, GermanyDepartment of History, Philosophy and Judaic Studies, The Open University of Israel, Raanana 43107, IsraelSourasky Medical Center, Clinical Biochemistry Laboratory, Tel Aviv 6423906, IsraelSourasky Medical Center, Clinical Biochemistry Laboratory, Tel Aviv 6423906, IsraelSourasky Medical Center, Clinical Biochemistry Laboratory, Tel Aviv 6423906, IsraelDepartment of Plant Biology, Braunschweig University of Technology, 38114 Braunschweig, GermanyDepartment of Plant Biology, Braunschweig University of Technology, 38114 Braunschweig, GermanyDepartment of Plant Biology, Braunschweig University of Technology, 38114 Braunschweig, GermanyDepartment of Genetics and Metabolic Diseases, Ziv Medical Center, Safed 13100, IsraelInstitute of Human Genetics, Western Galilee Hospital-Nahariya, Nahariya 22100, IsraelInstitute of Human Genetics, Western Galilee Hospital-Nahariya, Nahariya 22100, IsraelDepartment of Pathological Biochemistry, Medicine III, Medical Faculty, Technische Universitaet Dresden, 01062 Dresden, GermanyDay Hospitalization Center, Schneider Children’s Hospital, Petach-Tikva 4920235, IsraelMedical Clinic, Clalit Health Services, Tuba-Zangariyye 1231000, IsraelDepartment of Pediatrics, Soroka Medical Center, Beer Sheva 8457108, IsraelDepartment of Pediatrics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, IsraelClassical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the <i>XDH</i> (type I) or <i>MOCOS</i> (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 <i>XDH</i> gene and c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)) in the <i>MOCOS</i> 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.https://www.mdpi.com/2227-9059/9/7/788xanthinuria<i>XDH</i><i>MOCOS</i>heterologous protein expressionYemenite JewsArabs |
| spellingShingle | Hava Peretz Ayala Lagziel Florian Bittner Mustafa Kabha Meirav Shtauber-Naamati Vicki Zhuravel Sali Usher Steffen Rump Silke Wollers Bettina Bork Hanna Mandel Tzipora Falik-Zaccai Limor Kalfon Juergen Graessler Avraham Zeharia Nasser Heib Hannah Shalev Daniel Landau David Levartovsky Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects Biomedicines xanthinuria <i>XDH</i> <i>MOCOS</i> heterologous protein expression Yemenite Jews Arabs |
| title | Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects |
| title_full | Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects |
| title_fullStr | Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects |
| title_full_unstemmed | Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects |
| title_short | Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects |
| title_sort | classical xanthinuria in nine israeli families and two isolated cases from germany molecular biochemical and population genetics aspects |
| topic | xanthinuria <i>XDH</i> <i>MOCOS</i> heterologous protein expression Yemenite Jews Arabs |
| url | https://www.mdpi.com/2227-9059/9/7/788 |
| work_keys_str_mv | AT havaperetz classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT ayalalagziel classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT florianbittner classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT mustafakabha classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT meiravshtaubernaamati classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT vickizhuravel classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT saliusher classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT steffenrump classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT silkewollers classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT bettinabork classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT hannamandel classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT tziporafalikzaccai classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT limorkalfon classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT juergengraessler classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT avrahamzeharia classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT nasserheib classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT hannahshalev classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT daniellandau classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects AT davidlevartovsky classicalxanthinuriainnineisraelifamiliesandtwoisolatedcasesfromgermanymolecularbiochemicalandpopulationgeneticsaspects |