A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders.
A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders.
复制标题
三角头畸形和神经发育障碍中反复出现的 PJA1 变异。
DOI：
10.1002/acn3.51093
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发表时间：
2020
影响因子：
5.3
通讯作者：
Yamakawa Kazuhiro
中科院分区：
文献类型：
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作者：
Suzuki Toshimitsu;Suzuki Toshifumi;Raveau Matthieu;Miyake Noriko;Sudo Genki;Tsurusaki Yoshinori;Watanabe Takaki;Sugaya Yuki;.....Kano Masanobu;Shimoji Takeyoshi;Matsumoto Naomichi;Yamakawa Kazuhiro
目的神经发育障碍(NDDS)常与癫痫或颅面畸形相关。最近的大规模DNA分析确定了数百个NDDS的候选基因，但很大一部分病例仍然无法解释。方法我们对包括51例三角头畸形在内的95例NDD患者进行了外显子组测序，随后对另外463名NDD患者进行了靶向测序，体外功能分析，以及体内自闭症谱系障碍(ASD)样表型和癫痫相关表型的评估。结果我们在9个新基因中发现了新的截断变异体：CYP1A1、C14orf119、FLI1、CYB5R4、SEL1L2、RAB11FIP2、ZMNDY8、ZNF143和MSX2。MSX2变异已经在颅脑畸形患者中被描述，我们现在的MSX2去新截断变异的患者表现为颅脑脊膜膨出和部分癫痫。已知MSX2蛋白被E3泛素连接酶PJA1泛素化，有趣的是，我们在7名日本NDD患者中发现了PJA1hemizygous p.Arg376Cys变体；5名三角头畸形患者和1名部分癫痫患者，886名日本对照个体中没有该变体。携带P.Arg365Cys的Pja1敲入小鼠，相当于人类中的p.Arg376Cys，显示出显著的PJA1蛋白含量减少，表明该变体的功能丧失。Pja1基因敲除小鼠在隔离诱导的超声波发声中表现出中度缺陷，并增加了对戊四氮的易感性。这些新的发现提出了候选基因，包括与面部畸形和/或癫痫相关的JAP1MSX2基因。
ObjectiveNeurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large‐scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs.MethodsWe performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variantin vitro,and evaluations of autism spectrum disorder (ASD)‐like phenotypes and seizure‐related phenotypesin vivo.ResultsWe identifiedde novotruncation variants in nine novel genes;CYP1A1,C14orf119,FLI1,CYB5R4,SEL1L2, RAB11FIP2, ZMYND8, ZNF143,andMSX2. MSX2variants have been described in patients with cranial malformations, and our present patient with theMSX2 de novotruncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found aPJA1hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886 Japanese control individuals.Pja1knock‐in mice carrying p.Arg365Cys, which is equivalent to p.Arg376Cys in human, showed a significant decrease in PJA1 protein amount, suggesting a loss‐of‐function effect of the variant.Pja1knockout mice displayed moderate deficits in isolation‐induced ultrasonic vocalizations and increased seizure susceptibility to pentylenetetrazole.InterpretationThese findings propose novel candidate genes includingPJA1andMSX2for NDDs associated with craniofacial abnormalities and/or epilepsy.