PUBLICATION
CIAO1 and MMS19 deficiency: a lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders
- Authors
- 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., Berman, J.N., Dyment, D., Vaz, F.M., Wassermann, W.W., Houtkooper, R.H., van Kuilenburg, A.B.P.
- ID
- ZDB-PUB-240227-9
- Date
- 2024
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 26(6): 101104 (Journal)
- Registered Authors
- Ban, Kevin, Berman, Jason, Ekker, Marc, Pena, Izabella, Prykhozhij, Sergey, Saxena, Vishal
- Keywords
- CIAO1 and MMS19, Iron-sulfur clusters, cofactor, infection, neurodegeneration
- MeSH Terms
-
- Microcephaly/genetics
- Microcephaly/pathology
- Male
- Metallochaperones
- Infant
- PubMed
- 38411040 Full text @ Genet. Med.
Abstract
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.
Genes / Markers
Figure Gallery (5 images)
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping