Identification of a novel variant of the ciliopathic gene FUZZY associated with craniosynostosis

William B. Barrell, Hadeel Adel Al-Lami, Jacqueline A.C. Goos, Sigrid M.A. Swagemakers, Marieke van Dooren, Elena Torban, Peter J. van der Spek, Irene M.J. Mathijssen, Karen J. Liu*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)
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Craniosynostosis is a birth defect occurring in approximately one in 2000 live births, where premature fusion of the cranial bones inhibits growth of the skull during critical periods of brain development. The resulting changes in skull shape can lead to compression of the brain, causing severe complications. While we have some understanding of the molecular pathology of craniosynostosis, a large proportion of cases are of unknown genetic aetiology. Based on studies in mouse, we previously proposed that the ciliopathy gene Fuz should be considered a candidate craniosynostosis gene. Here, we report a novel variant of FUZ (c.851 G > C, p.(Arg284Pro)) found in monozygotic twins presenting with craniosynostosis. To investigate whether Fuz has a direct role in regulating osteogenic fate and mineralisation, we cultured primary osteoblasts and mouse embryonic fibroblasts (MEFs) from Fuz mutant mice. Loss of Fuz resulted in increased osteoblastic mineralisation. This suggests that FUZ protein normally acts as a negative regulator of osteogenesis. We then used Fuz mutant MEFs, which lose functional primary cilia, to test whether the FUZ p.(Arg284Pro) variant could restore FUZ function during ciliogenesis. We found that expression of the FUZ p.(Arg284Pro) variant was sufficient to partially restore cilia numbers, but did not mediate a comparable response to Hedgehog pathway activation. Together, this suggests the osteogenic effects of FUZ p.(Arg284Pro) do not depend upon initiation of ciliogenesis.

Original languageEnglish
Pages (from-to)282-290
Number of pages9
JournalEuropean Journal of Human Genetics
Issue number3
Early online date1 Nov 2021
Publication statusPublished - Mar 2022

Bibliographical note

Funding Information:
This study was funded by grants from the EPSRC (WBB/KJL), BBSRC BB/R015953/1 (KJL) and studentship from the Iraq Higher Council for Education (HAA). Bioinformatics data analysis and whole genome sequencing infrastructure has been funded from grants at Erasmus medical including CTMM Biochip, CTMM Trait, ZonMW/NWO Genetics First, H2020 Bigmedilytics and the Erasmus Center for Data Analytics (ECDA).

Publisher Copyright:
© 2021, The Author(s).


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