CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.
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van Karnebeek Clara D M, Tarailo-Graovac Maja, Leen René, Meinsma Rutger, Correard Solenne, Jansen-Meijer Judith, Prykhozhij Sergey V, Pena Izabella A, Ban Kevin, Schock Sarah, Saxena Vishal, Pras-Raves Mia L, Drögemöller Britt I, Grootemaat Anita E, van der Wel Nicole N, Dobritzsch Doreen, Roseboom Winfried, Schomakers Bauke V, Jaspers Yorrick R J, Zoetekouw Lida, Roelofsen Jeroen, Ferreira Carlos R, van der Lee Robin, Ross Colin J, Kochan Jakub, McIntyre Rebecca L, van Klinken Jan B, van Weeghel Michel, Kramer Gertjan, Weschke Bernhard, Labrune Philippe, Willemsen Michèl A, Riva Daria, Garavaglia Barbara, Moeschler John B, Filiano James J, Ekker Marc, Berman Jason N, Dyment David, Vaz Frédéric M, Wasserman Wyeth W, Houtkooper Riekelt H, van Kuilenburg André B P
Аннотация
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.