TY - JOUR
T1 - CIAO1 and MMS19 deficiency
T2 - A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders
AU - van Karnebeek, Clara D. M.
AU - Tarailo-Graovac, Maja
AU - Leen, René
AU - Meinsma, Rutger
AU - Correard, Solenne
AU - Jansen-Meijer, Judith
AU - Prykhozhij, Sergey V.
AU - Pena, Izabella A.
AU - Ban, Kevin
AU - Schock, Sarah
AU - Saxena, Vishal
AU - Pras-Raves, Mia L.
AU - Drögemöller, Britt I.
AU - Grootemaat, Anita E.
AU - van der Wel, Nicole N.
AU - Dobritzsch, Doreen
AU - Roseboom, Winfried
AU - Schomakers, Bauke V.
AU - Jaspers, Yorrick R. J.
AU - Zoetekouw, Lida
AU - Roelofsen, Jeroen
AU - Ferreira, Carlos R.
AU - van der Lee, Robin
AU - Ross, Colin J.
AU - Kochan, Jakub
AU - McIntyre, Rebecca L.
AU - van Klinken, Jan B.
AU - van Weeghel, Michel
AU - Kramer, Gertjan
AU - Weschke, Bernhard
AU - Labrune, Philippe
AU - Willemsen, Michèl A.
AU - Riva, Daria
AU - Garavaglia, Barbara
AU - Moeschler, John B.
AU - Filiano, James J.
AU - Ekker, Marc
AU - Berman, Jason N.
AU - Dyment, David
AU - Vaz, Frédéric M.
AU - Wassermann, Wyeth W.
AU - Houtkooper, Riekelt H.
AU - van Kuilenburg, André B. P.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/6/1
Y1 - 2024/6/1
N2 - Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. Results: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. Conclusion: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.
AB - Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. Results: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. Conclusion: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.
KW - CIAO1 and MMS19
KW - Cofactor
KW - Infection
KW - Iron-sulfur clusters
KW - Neurodegeneration
UR - https://www.scopus.com/pages/publications/85189951629
U2 - 10.1016/j.gim.2024.101104
DO - 10.1016/j.gim.2024.101104
M3 - Article
C2 - 38411040
SN - 1098-3600
VL - 26
JO - Genetics in medicine
JF - Genetics in medicine
IS - 6
M1 - 101104
ER -