Gene of the Month – December: CIROP

CIROP is a newly discovered gene which has an essential function in developing and distinguishing left and right in the human body. It is one of five genes that a team of scientists led by Bruno Reversade at the Genome Institute of Singapore (GIS) has identified to directly contribute to left-right asymmetry. The genes have been lost twice in the course of vertebrate evolution and their expression correlates with the presence of motile cilia at the left-right organizer in certain vertebrates. At this specific region of the embryo, motile cilia generate a directional flow of extracellular fluids, thus breaking symmetry. The researchers named the newly discovered gene therefore ciliated left–right organizer metallopeptide (CIROP). Starting with zebrafish, they performed extensive studies across several vertebral species, including frog and mice, and also used genome editing for gene knockout to investigate the encoded protein’s function.

While the human body superficially appears symmetrical, for example with regard to limbs, a deeper look reveals a different picture: internal organs like heart, liver or spleen are asymmetrically placed. Their placement is governed during early embryonic development, when the left-right axis is specified by the left-right organizer, orchestrated by a signalling cascade. If this is not properly achieved, severe birth anomalies like congenital heart defects or misplacement of internal organs along the left-right axis may occur. In the light of the findings of their evolutionary analysis of genomes, the researchers searched for relevant genetic variants in patients and identified autosomal recessive CIROP variants in 21 patients with misarranged organs or congenital heart defects.

The results of the study have been published in Nature Genetics.

Szenker-Ravi E, Ott T, Khatoo M, … Reversade B. Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates. Nat Genet. 2021 Dec 13. doi: 10.1038/s41588-021-00970-4. Epub ahead of print.

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