期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 30, 期 3, 页码 282-290出版社
SPRINGERNATURE
DOI: 10.1038/s41431-021-00988-6
关键词
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资金
- EPSRC
- BBSRC [BB/R015953/1]
- Iraq Higher Council for Education
- Erasmus medical
- CTMM Biochip
- CTMM Trait
- ZonMW/NWO Genetics First
- H2020 Bigmedilytics
- Erasmus Center for Data Analytics (ECDA)
- BBSRC [BB/R015953/1] Funding Source: UKRI
Craniosynostosis is a rare birth defect that can lead to severe complications such as compression of the brain. Studies suggest a variant of the FUZ gene may be associated with craniosynostosis, with loss of FUZ function leading to increased osteoblastic mineralisation. However, the FUZ variant's effects on ciliogenesis are limited.
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.
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