A prevalent MOCS2 variant in the Roma population is associated with a novel mild form of molybdenum cofactor deficiency

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023728%3A_____%2F25%3AN0000001" target="_blank" >RIV/00023728:_____/25:N0000001 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00023728:_____/25:N0000002 RIV/00216208:11110/25:10500164 RIV/00064165:_____/25:10500164

Výsledek na webu

<a href="https://doi.org/10.1007/s00431-025-06335-x" target="_blank" >https://doi.org/10.1007/s00431-025-06335-x</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00431-025-06335-x" target="_blank" >10.1007/s00431-025-06335-x</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A prevalent MOCS2 variant in the Roma population is associated with a novel mild form of molybdenum cofactor deficiency

Popis výsledku v původním jazyce

Xanthinurias are rare inherited disorders of purine metabolism. Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. Here, we described five Roma patients from four unrelated families with hypouricemia, accumulation of xanthine/hypoxanthine, deficiency of xanthine oxidase activity, variable age of diagnosis, and only asymptomatic or mild clinical course. Whole exome sequencing was performed on all probands, aged 3 to 43 years, due to lack of genetic confirmation for xanthinuria types I and II. The causality of the putative pathogenic variant was confirmed by analysis of sulfite and related metabolites and in vitro functional characterization of metal-binding pterin (MPT) synthesis and protein complex formation. Considering the rarity of the condition and recessive inheritance, 34 candidate variants were identified after filtering out allele frequency threshold in non-Finnish Europeans. An ultra-rare MOCS2 variant rs776441627 in two overlapping reading frames (c.244A > T (NM_176806.4; p.Ile82Phe) = c.57A > T (NM_004531.5; p.Leu19Phe)) segregated with the disease in all five patients (four homozygotes, one compound heterozygote). The variant has an allele frequency of 3.6% in a Roma population control group. Functional characterization revealed the significantly decreased MPT synthesis activity and confirmed the causality of rs776441627 in MoCD.  The rs776441627 is a functional variant for MoCD with a mild to asymptomatic clinical phenotype and fully penetrant biochemical phenotype. Hypouricemia should be considered in the differential diagnostic algorithm of pediatric and adult patients with neurological symptoms, and MOCS2 should be considered in gene panels for xanthinuria screening.  Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. • The majority of patients with xanthinuria III present with classical early-onset MoCD due to autosomal recessive variants in the MOCS1 gene, manifesting severe progressive neurological complications during the first postnatal days. • To date, approximately 40 patients with MoCD due to pathogenic MOCS2 variants have been reported; most were diagnosed during the neonatal period with intractable seizures and feeding disorders.  A novel ultra-rare variant, rs776441627, located in two overlapping reading frames of the MOCS2, was identified in five Roma patients presenting a mild to asymptomatic clinical MoCD phenotype and a fully penetrant biochemical phenotype. • Functional studies of p.Ile82Phe (small MOCS2A subunit) and p.Leu19Phe (large MOCS2B subunit) demonstrate a strong reduction in molydopterin synthase complex formation and activity, consistent with the changes in biomarkers of MoCD observed in affected individuals. • The rs776441627 variant shows significantly elevated frequency among the Roma population, highlighting the importance of considering ethnic background in the differential diagnosis of MoCD. • Hypouricemia may provide an initial, generally available biochemical key marker indicator of molybdenum cofactor deficiency.

Název v anglickém jazyce

A prevalent MOCS2 variant in the Roma population is associated with a novel mild form of molybdenum cofactor deficiency

Popis výsledku anglicky

Xanthinurias are rare inherited disorders of purine metabolism. Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. Here, we described five Roma patients from four unrelated families with hypouricemia, accumulation of xanthine/hypoxanthine, deficiency of xanthine oxidase activity, variable age of diagnosis, and only asymptomatic or mild clinical course. Whole exome sequencing was performed on all probands, aged 3 to 43 years, due to lack of genetic confirmation for xanthinuria types I and II. The causality of the putative pathogenic variant was confirmed by analysis of sulfite and related metabolites and in vitro functional characterization of metal-binding pterin (MPT) synthesis and protein complex formation. Considering the rarity of the condition and recessive inheritance, 34 candidate variants were identified after filtering out allele frequency threshold in non-Finnish Europeans. An ultra-rare MOCS2 variant rs776441627 in two overlapping reading frames (c.244A > T (NM_176806.4; p.Ile82Phe) = c.57A > T (NM_004531.5; p.Leu19Phe)) segregated with the disease in all five patients (four homozygotes, one compound heterozygote). The variant has an allele frequency of 3.6% in a Roma population control group. Functional characterization revealed the significantly decreased MPT synthesis activity and confirmed the causality of rs776441627 in MoCD.  The rs776441627 is a functional variant for MoCD with a mild to asymptomatic clinical phenotype and fully penetrant biochemical phenotype. Hypouricemia should be considered in the differential diagnostic algorithm of pediatric and adult patients with neurological symptoms, and MOCS2 should be considered in gene panels for xanthinuria screening.  Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. • The majority of patients with xanthinuria III present with classical early-onset MoCD due to autosomal recessive variants in the MOCS1 gene, manifesting severe progressive neurological complications during the first postnatal days. • To date, approximately 40 patients with MoCD due to pathogenic MOCS2 variants have been reported; most were diagnosed during the neonatal period with intractable seizures and feeding disorders.  A novel ultra-rare variant, rs776441627, located in two overlapping reading frames of the MOCS2, was identified in five Roma patients presenting a mild to asymptomatic clinical MoCD phenotype and a fully penetrant biochemical phenotype. • Functional studies of p.Ile82Phe (small MOCS2A subunit) and p.Leu19Phe (large MOCS2B subunit) demonstrate a strong reduction in molydopterin synthase complex formation and activity, consistent with the changes in biomarkers of MoCD observed in affected individuals. • The rs776441627 variant shows significantly elevated frequency among the Roma population, highlighting the importance of considering ethnic background in the differential diagnosis of MoCD. • Hypouricemia may provide an initial, generally available biochemical key marker indicator of molybdenum cofactor deficiency.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30209 - Paediatrics

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

EUROPEAN JOURNAL OF PEDIATRICS

ISSN

0340-6199

e-ISSN

1432-1076

Svazek periodika

184

Číslo periodika v rámci svazku

Art. Nr. 499

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

13

Strana od-do

1-13

Kód UT WoS článku

001536395200002

EID výsledku v databázi Scopus

2-s2.0-105011340431