Linking the Role of Iron-Sulfur Enzymes to Human Health and Disease

DNA sequencing is visualized as rows of rectangles in shades of purple, orange, and gold along the entire background. On the right side, a DNA strand runs vertical.

Iron is an essential trace element for all living organisms and plays a crucial role in various physiological processes. This activity relies on iron-sulfur enzymes and related proteins that help recruit and assemble iron-sulfur clusters—all of which occurs independently in the cytoplasm and mitochondria of a cell.

The gene CIAO1 is an integral part of the “machinery” that in the cytoplasm helps assemble iron-sulfur clusters for enzymes involved in DNA and RNA metabolism, including DNA replication and repair within the cell nucleus. However, its precise role is not clear.
In a study from the Rouault Lab and collaborators, researchers discovered that mutations in the CIAO1 gene are responsible for a genetic disorder in people that causes a range of symptoms, including muscle weakness, learning difficulties, neurobehavioral issues, brain iron overload, anemia with enlarged red cells, and gastrointestinal problems.
The team found that mutations in the CIAO1 gene impaired the ability of cells to deliver iron-sulfur clusters to proteins that function in the nucleus. As a result, multiple types of enzymes that rely on iron-sulfur cofactors could not function properly, including DNA helicases, polymerases, and repair enzymes.
In a series of experiments using cells derived from patients, the team restored typical CIAO1 gene expression, which reversed problems that were observed at the cellular level.
Overall, the study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the iron-sulfur assembly pathways in human health and disease.

Reference

Maio N, Orbach R, Zaharieva IT, Töpf A, Donkervoort S, Munot P, Mueller J, Willis T, Verma S, Peric S, Krishnakumar D, Sudhakar S, Foley AR, Silverstein S, Douglas G, Pais L, DiTroia S, Grunseich C, Hu Y, Sewry C, Sarkozy A, Straub V, Muntoni F, Rouault TA, Bönnemann CG. CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes. Journal of Clinical Investigation. DOI: 10.1172/JCI179559 (2024)

Learn more about the Molecular Medicine Group: https://www.nichd.nih.gov/about/org/dir/affinity-groups/MM.