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CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes
Nunziata Maio, … , Tracey A. Rouault, Carsten G. Bönnemann
Nunziata Maio, … , Tracey A. Rouault, Carsten G. Bönnemann
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e179559. https://doi.org/10.1172/JCI179559.
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Research Article Metabolism Muscle biology Article has an altmetric score of 2

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes

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Abstract

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.

Authors

Nunziata Maio, Rotem Orbach, Irina T. Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, A. Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey A. Rouault, Carsten G. Bönnemann

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Figure 3

Brain MRI of P2 demonstrating evolving increased iron deposition in deep nuclei of the brain.

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Brain MRI of P2 demonstrating evolving increased iron deposition in deep...
Brain MRI of P2 performed at age 8 years 6 months shows normal anatomy and susceptibility signals. Brain MRI acquired at age 14 years 6 months shows increased, atypical-for-age susceptibility of bilateral globus pallidus (interna and externa with laminar sparing, upper row), substantia nigra (middle row), red nucleus (middle row), and dentate nucleus (lower row). The increased mineralization is evidenced as hypointense signal on T2 and SWI, and hyperintensity on QSM. The areas of interest are denoted by asterisks, with their color coding corresponding to the regions specified in the anatomical reference on the left. Of note, mild, diffuse cerebral and cerebellar volume reduction was also apparent when compared with the earlier scan. The left panel is displayed for anatomical reference.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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