CIAO1 and MMS19 deficiency : a lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders

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 two 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. Genome sequencing identified compound heterozygosity in two patients for missense variants in CIAO1 and homozygosity for an in-frame 3-nucleotide deletion in MMS19 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.