The CIROP-ergic pathway
The CIROP-ergic pathway
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The CIROP gene has a singular pattern of gene inactivation across vertebrate species. While it is present in humans and mice, its homologs in cetartiodactyla have acquired biallelic loss-of-function mutations, indicating that no selective pressure exists to maintain CIROP in these species. According to C. Gordon and colleagues a similar situation exists for MMP21 which exists in select vertebrates, including fish and amphibians, but has been lost in all bird and reptile species. This peculiar, and repeated, CIROP & MMP21 gene disappearance/inactivation across diverse phyla appears to coincide with the loss of motile cilia in central cells of the LRO in those animals that do not use cilia-driven flow to impart LR polarity.
The CIROP gene has a singular pattern of gene inactivation across vertebrate species. While it is present in humans and mice, its homologs in cetartiodactyla have acquired biallelic loss-of-function mutations, indicating that no selective pressure exists to maintain CIROP in these species. According to C. Gordon and colleagues a similar situation exists for MMP21 which exists in select vertebrates, including fish and amphibians, but has been lost in all bird and reptile species. This peculiar, and repeated, CIROP & MMP21 gene disappearance/inactivation across diverse phyla appears to coincide with the loss of motile cilia in central cells of the LRO in those animals that do not use cilia-driven flow to impart LR polarity.
Based on this initial observation, we hypothesized that CIROP must represent, and belong to, a larger group of genes that together constitute a pathway specifically needed for motile cilia-dependent LR patterning. We thus searched for genes that, like CIROP are present in fish, frogs, primates, rodents and odd-toed ungulates (Euarchontoglires and Zoomata) but are absent, or inactivated, in birds, reptiles and even-toed mammals (Sauria and Artiofabula)
Based on this initial observation, we hypothesized that CIROP must represent, and belong to, a larger group of genes that together constitute a pathway specifically needed for motile cilia-dependent LR patterning. We thus searched for genes that, like CIROP are present in fish, frogs, primates, rodents and odd-toed ungulates (Euarchontoglires and Zoomata) but are absent, or inactivated, in birds, reptiles and even-toed mammals (Sauria and Artiofabula)
This search produced three additional genes, all of which are annotated to contain a signal peptide at their N-terminus. Two of these, PKD1L1 and DAND5, are already known to be needed for LR patterning in various model organisms. The disappearance of DAND5 in birds and reptiles was already documented, while PKD1L1 had not been shown previously to have been lost in birds, reptiles and cetartiodactyla. One additional gene CIROP was identified, encoding a putative secreted proteins previously named C1orf127. Like MMP21, CIROP and CIROZ are both present in fish, amphibians and odd-toed mammals, including rodents and humans, but are absent or mutated in birds, reptiles and cetartiodactyla. CIROZ appears to have undergone pseudogenization in frogs and fish as its inactivation produces no phenotype.
This search produced three additional genes, all of which are annotated to contain a signal peptide at their N-terminus. Two of these, PKD1L1 and DAND5, are already known to be needed for LR patterning in various model organisms. The disappearance of DAND5 in birds and reptiles was already documented, while PKD1L1 had not been shown previously to have been lost in birds, reptiles and cetartiodactyla. One additional gene CIROP was identified, encoding a putative secreted proteins previously named C1orf127. Like MMP21, CIROP and CIROZ are both present in fish, amphibians and odd-toed mammals, including rodents and humans, but are absent or mutated in birds, reptiles and cetartiodactyla. CIROZ appears to have undergone pseudogenization in frogs and fish as its inactivation produces no phenotype.
To test if CIROP was involved in establishing the LR axis in humans, we screened for germline CIROP mutations using targeted sequencing in a cohort of 186 index cases with CHDs. We identified germline homozygous CIROP variants in seven cases of CHD associated with HTX in Families 1–7. We further identified CIROP mutations by exome or targeted sequencing in five additional families segregating HTX (Families 8–12). All germline variants were confirmed by Sanger sequencing and found to segregate fully with the phenotype according to an autosomal recessive mode of inheritance. Of the 21 cases presenting with congenital HTX, 8 had situs solitus with or without isolated dextrocardia, 5 had situs ambiguus, 8 had situs inversus totalis and nearly all had CHDs. Similar to cirop mutant zebafish, no other ciliopathy-related phenotype was observed in CIROP-mutated patients, arguing that CIROP plays no role beyond early LR specification.
To test if CIROP was involved in establishing the LR axis in humans, we screened for germline CIROP mutations using targeted sequencing in a cohort of 186 index cases with CHDs. We identified germline homozygous CIROP variants in seven cases of CHD associated with HTX in Families 1–7. We further identified CIROP mutations by exome or targeted sequencing in five additional families segregating HTX (Families 8–12). All germline variants were confirmed by Sanger sequencing and found to segregate fully with the phenotype according to an autosomal recessive mode of inheritance. Of the 21 cases presenting with congenital HTX, 8 had situs solitus with or without isolated dextrocardia, 5 had situs ambiguus, 8 had situs inversus totalis and nearly all had CHDs. Similar to cirop mutant zebafish, no other ciliopathy-related phenotype was observed in CIROP-mutated patients, arguing that CIROP plays no role beyond early LR specification.
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