| Source: |
van Karnebeek, C D M, Tarailo-Graovac, M, Leen, R, Meinsma, R, Correard, S, Jansen-Meijer, J, Prykhozhij, S V, Pena, I A, Ban, K, Schock, S, Saxena, V, Pras-Raves, M L, Drögemöller, B I, Grootemaat, A E, van der Wel, N N, Dobritzsch, D, Roseboom, W, Schomakers, B V, Jaspers, Y R J, Zoetekouw, L, Roelofsen, J, Ferreira, C R, van der Lee, R, Ross, C J, Kochan, J, McIntyre, R L, van Klinken, J B, van Weeghel, M, Kramer, G, Weschke, B, Labrune, P, Willemsen, M A, Riva, D, Garavaglia, B, Moeschler, J B, Filiano, J J, Ekker, M, .... |
| Description: |
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. |