Abigail O. Smith

University of Massachusetts Chan Medical School

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Gregory J. Pazour

University of Massachusetts Chan Medical School

Julie A. Jonassen

University of Massachusetts Chan Medical School

Kenley M. Preval

University of Massachusetts Chan Medical School

William Frantz

University of Massachusetts Chan Medical School

Miriam Schmidts

University of Freiburg

Yvonne J. K. Edwards

University of Massachusetts Chan Medical School

Roger J. Davis

University of Massachusetts Chan Medical School

Thibaut Eguether

Inserm

Cecilia Lo

University of Pittsburgh

Julia Hoefele

Klinikum rechts der Isar

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University of Massachusetts Chan Medical School

University College London

Harvard University

Massachusetts General Hospital

UMass Memorial Medical Center

Massachusetts Academy of Math and Science

Radboud University Nijmegen

Howard Hughes Medical Institute

Radboud University Medical Center

Radboud Institute for Molecular Life Sciences

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IFT74variants cause skeletal ciliopathy and motile cilia defects in mice and humans

medRxiv (Cold Spring Harbor Laboratory) (2023)

Zeineb Bakey Oscar A. Cabrera Julia Hoefele Dinu Antony Kaman Wu

Motile and non-motile cilia are critical to mammalian development and health. Assembly of these organelles depends on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). A series of human and mouse IFT74 variants were studied to understand the function of this IFT subunit. Humans missing exon 2, which codes for the first 40 residues, presented an unusual combination of ciliary chondrodysplasia and mucociliary clearance disorders while individuals carrying biallelic splice site variants developed a lethal skeletal chondrodysplasia. In mice, variants thought to remove all Ift74 function, completely block ciliary assembly and result in midgestational lethality. A mouse allele that removes the first 40 amino acids, analogous to the human exon 2 deletion, results in a motile cilia phenotype with mild skeletal abnormalities. 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 could account for the motile cilia phenotype observed in human and mice.

Ciliopathy

Motile cilium

10.1101/2023.02.23.23286106

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