In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 19, No. 6 ( 2023-6-14), p. e1010796-
Abstract:
Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010796
DOI:
10.1371/journal.pgen.1010796.g001
DOI:
10.1371/journal.pgen.1010796.g002
DOI:
10.1371/journal.pgen.1010796.g003
DOI:
10.1371/journal.pgen.1010796.g004
DOI:
10.1371/journal.pgen.1010796.g005
DOI:
10.1371/journal.pgen.1010796.g006
DOI:
10.1371/journal.pgen.1010796.g007
DOI:
10.1371/journal.pgen.1010796.g008
DOI:
10.1371/journal.pgen.1010796.g009
DOI:
10.1371/journal.pgen.1010796.t001
DOI:
10.1371/journal.pgen.1010796.t002
DOI:
10.1371/journal.pgen.1010796.s001
DOI:
10.1371/journal.pgen.1010796.s002
DOI:
10.1371/journal.pgen.1010796.s003
DOI:
10.1371/journal.pgen.1010796.s004
DOI:
10.1371/journal.pgen.1010796.s005
DOI:
10.1371/journal.pgen.1010796.s006
DOI:
10.1371/journal.pgen.1010796.s007
DOI:
10.1371/journal.pgen.1010796.s008
DOI:
10.1371/journal.pgen.1010796.s009
DOI:
10.1371/journal.pgen.1010796.s010
DOI:
10.1371/journal.pgen.1010796.s011
DOI:
10.1371/journal.pgen.1010796.s012
DOI:
10.1371/journal.pgen.1010796.s013
DOI:
10.1371/journal.pgen.1010796.s014
DOI:
10.1371/journal.pgen.1010796.s015
DOI:
10.1371/journal.pgen.1010796.s016
DOI:
10.1371/journal.pgen.1010796.s017
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2186725-2
Bookmarklink
