Identification of a novel variant of the ciliopathic gene FUZZY associated with craniosynostosis.
Identification of a novel variant of the ciliopathic gene FUZZY associated with craniosynostosis.
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DOI：
10.1038/s41431-021-00988-6
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Liu KJ
中科院分区：
文献类型：
--
作者：
Barrell WB;Adel Al-Lami H;Goos JAC;Swagemakers SMA;van Dooren M;Torban E;van der Spek PJ;Mathijssen IMJ;Liu KJ
颅缝早闭症是一种出生缺陷，大约每2000个活产婴儿中就有一个，在大脑发育的关键时期，颅骨的过早融合会抑制头骨的生长。由此产生的颅骨形状的变化可能导致大脑受压，导致严重的并发症。虽然我们对颅缝早闭的分子病理学有一定的了解，但很大一部分病例的遗传病因尚不清楚。基于在小鼠中的研究，我们先前提出纤毛病基因Fuz应被认为是颅缝早闭症的候选基因。在这里，我们报告了FUZ的一种新变体（c.851 G> C，p.（Arg284Pro））在表现为颅缝早闭的单卵双胞胎中发现。为了研究Fuz是否在调节成骨命运和矿化中具有直接作用，我们培养了Fuz突变小鼠的原代成骨细胞和小鼠胚胎成纤维细胞（MEFs）。Fuz缺失导致成骨细胞矿化增加。这表明FUZ蛋白通常作为骨生成的负调节剂。然后，我们使用Fuz突变MEFs，失去功能性初级纤毛，以测试是否FUZ p。（Arg284Pro）突变体可以恢复纤毛发生过程中FUZ的功能。我们发现FUZ p.（Arg284 Pro）变体足以部分恢复纤毛数量，但不介导对Hedgehog途径激活的可比响应。总之，这表明FUZ p的成骨作用。（Arg284Pro）不依赖于纤毛发生的起始。
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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影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
4
作者：
Daste, Frederic;Galli, Thierry;Tareste, David
通讯作者：
Tareste, David
影响因子：
3.1
作者：
Cornelissen, Martijn;den Ottelander, Bianca;Mathijssen, Irene
通讯作者：
Mathijssen, Irene
影响因子：
7.2
作者：
Schock, Elizabeth N.;Brugmann, Samantha A.
通讯作者：
Brugmann, Samantha A.
DOI：
10.4161/rdis.27109
发表时间：
2013
期刊：
Rare diseases (Austin, Tex.)
影响因子：
--
作者：
Yannakoudakis BZ;Liu KJ
通讯作者：
Liu KJ