TY - JOUR
T1 - CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans
AU - Szenker-Ravi, Emmanuelle
AU - Ott, Tim
AU - Yusof, Amirah
AU - Chopra, Maya
AU - Khatoo, Muznah
AU - Pak, Beatrice
AU - Xuan Goh, Wei
AU - Beckers, Anja
AU - Brady, Angela F.
AU - Ewans, Lisa J.
AU - Djaziri, Nabila
AU - Almontashiri, Naif A.M.
AU - Alghamdi, Malak Ali
AU - Alharby, Essa
AU - Dasouki, Majed
AU - Romo, Lindsay
AU - Tan, Wen Hann
AU - Maddirevula, Sateesh
AU - Alkuraya, Fowzan S.
AU - Giordano, Jessica L.
AU - Alkelai, Anna
AU - Wapner, Ronald J.
AU - Stals, Karen
AU - Alfadhel, Majid
AU - Alswaid, Abdulrahman Faiz
AU - Bogusch, Susanne
AU - Schafer-Kosulya, Anna
AU - Vogel, Sebastian
AU - Vick, Philipp
AU - Schweickert, Axel
AU - Wakeling, Matthew
AU - Moreau de Bellaing, Anne
AU - Alshamsi, Aisha M.
AU - Sanlaville, Damien
AU - Mbarek, Hamdi
AU - Saad, Chadi
AU - Ellard, Sian
AU - Eisenhaber, Frank
AU - Tripolszki, Kornelia
AU - Beetz, Christian
AU - Bauer, Peter
AU - Gossler, Achim
AU - Eisenhaber, Birgit
AU - Blum, Martin
AU - Bouvagnet, Patrice
AU - Bertoli-Avella, Aida
AU - Amiel, Jeanne
AU - Gordon, Christopher T.
AU - Reversade, Bruno
N1 - Publisher Copyright:
© 2024
PY - 2025/2/6
Y1 - 2025/2/6
N2 - Four genes—DAND5, PKD1L1, MMP21, and CIROP—form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO). We find here that CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization. We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects. While the knockout of Ciroz in mice also leads to situs anomalies, we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies. Moreover, CIROZ is absent or obsolete in select animals with motile cilia at their LRO, including Carnivora, Atherinomorpha fish, or jawless vertebrates. In summary, this evo-devo study identifies CIROZ as an essential gene for breaking bilateral embryonic symmetry in humans and mice, whereas we witness its contemporary pseudogenization in discrete vertebrate species.
AB - Four genes—DAND5, PKD1L1, MMP21, and CIROP—form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO). We find here that CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization. We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects. While the knockout of Ciroz in mice also leads to situs anomalies, we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies. Moreover, CIROZ is absent or obsolete in select animals with motile cilia at their LRO, including Carnivora, Atherinomorpha fish, or jawless vertebrates. In summary, this evo-devo study identifies CIROZ as an essential gene for breaking bilateral embryonic symmetry in humans and mice, whereas we witness its contemporary pseudogenization in discrete vertebrate species.
KW - C1orf127
KW - CIROP
KW - CIROZ
KW - DAND5
KW - evo-devo
KW - gene loss
KW - heterotaxy
KW - laterality
KW - left-right organizer
KW - MMP21
KW - motile cilia
KW - PKD1L1
KW - pseudogenization
KW - ZP-N
KW - ZP2
UR - http://www.scopus.com/inward/record.url?scp=85215574408&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2024.12.006
DO - 10.1016/j.ajhg.2024.12.006
M3 - Article
C2 - 39753129
AN - SCOPUS:85215574408
SN - 0002-9297
VL - 112
SP - 353
EP - 373
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -