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Updated: Jul 2, 2025
Modeling Age-Associated Neurodegenerative Diseases in Caenorhabditis elegans
Published on: August 15, 2020
CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly
Clara D M van Karnebeek1, Maja Tarailo-Graovac2, René Leen3
1Amsterdam UMC location University of Amsterdam, Departments of Pediatrics and Human Genetics, Emma Center for Personalized Medicine, Amsterdam, The Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, The Netherlands; Departments of Medical Genetics and Pediatrics, Centre for Molecular Medicine and Therapeutics, Faculty of Pharmaceutical Science, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; United for Metabolic Diseases, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
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.
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