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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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 2

Muscle MRI, histopathology, and ultrastructural findings.

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Muscle MRI, histopathology, and ultrastructural findings. (A) Anatomical...
(A) Anatomical reference. MRI scan positions are indicated with red lines on a human reference image. Figure 2A was created with BioRender.com. (B) Normal muscle MRI cross-sectional images showing anatomy of pelvic (top), thigh (middle), and lower leg (bottom) muscles. AL, adductor longus; AM, adductor magnus; BF, biceps femoris; EDL, extensor digitorum longus; Gmax, gluteus maximus; Gmed, gluteus medius; Gmin, gluteus minimus; Gr, gracilis; Il, iliacus; LG, lateral gastrocnemius; MG, medial gastrocnemius; PL, peroneus longus; RF, rectus femoris; Sa, sartorius; SM, semimembranosus; ST, semitendinosus; VI, vastus intermedius; TP, tibialis posterior; VL, vastus lateralis; VM, vastus medialis. (C) Axial muscle MRI images of P1 at age 17 years (proximal to distal) at pelvic, thigh, and calf levels showing diffuse fatty transformation (red arrows) greater in proximal muscles and more pronounced in the posterior thighs. (D) Quadriceps muscle biopsy from P2 at 6 years of age. H&E staining showed abnormal variation in fiber size, internal nuclei (small arrow), slight hypercontraction of fibers (green arrow), a focal area of cellularity possibly associated with necrosis (large black arrow), and slightly basophilic fibers (blue arrow). Scale bar: 100 μm. (E) Vastus lateralis muscle biopsy from P3 at 15 years of age. H&E staining shows abnormal variation in fiber size, necrotic fibers (*), increased number of internal nuclei (black arrow), increase in endomysial connective tissue, and endomysial cellularity (green arrow). Scale bar: 250 μm. (F) Combined cytochrome oxidase (COX) and succinic dehydrogenase (SDH) stains of quadriceps muscle from P2 at 6 years of age shows prominent mitochondria in several type 1 myofibers (arrows). Scale bar: 100 μm. (G) EM image of vastus medialis muscle biopsy from P1 at age 5 years and 10 months shows scattered clusters of morphologically abnormal mitochondria (arrows). Scale bar: 2 μm. (H) EM image of quadriceps muscle biopsy of P2 at 6 years of age shows morphologically abnormal, large mitochondria with whorled cristae (arrow). Scale bar: 500 nm. (I) Additional EM image from P1 shows large mitochondria with disoriented cristae with concentric arrangements (arrow). Scale bar: 500 nm.