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

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

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 1

Identification of biallelic CIAO1 variants in 4 independent patients with a neuromuscular condition of undefined etiology.

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Identification of biallelic CIAO1 variants in 4 independent patients wit...
(A) Proposed model for the biogenesis of ISCs in mammalian cells. De novo assembly of ISCs occurs upon the main scaffold protein ISCU by the coordinated action of a multiprotein complex, which consists of the cysteine desulfurase NFS1 and the accessory protein ISD11. The HSC20-HSPA9 cochaperone-chaperone complex interacts with ISCU to facilitate cluster transfer to recipient proteins. The functional unit of HSC20 is a dimer (15). A subset of recipient Fe-S proteins acquire their clusters directly from the HSC20-HSPA9-ISCU1 complex (15). In the cytoplasm, binding of HSC20 to the LYR motif of CIAO1 recruits the CIA-targeting complex, which is known to form a platform to which Fe-S recipients involved in DNA metabolism dock to acquire their clusters (13, 14). The Fe-S proteins shown in the model were all identified as HSC20 interacting partners (15) (i.e., NUBP2, GLRX3, CIAPIN1, ABCE1, ERCC2, POLD1, PRIM2, PPAT, ELP3, CPSF30, DDX11, etc.). (B) Diagram showing the country of origin of the 4 patients with biallelic CIAO1 variants. Recurring variants are shown in red and blue. The age when symptoms were first recognized (on the left) and the age at the latest clinical assessment (on the right) are shown at the bottom. Figure 1B was created with BioRender.com.