Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.
Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.
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DOI：
10.1126/sciadv.ade1463
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发表时间：
2023-03-10
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
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KMT5B（一种赖氨酸甲基转移酶）中的致病性变体与全面发育迟缓、大头畸形、自闭症和先天性异常相关（OMIM# 617788）。鉴于这种疾病的发现相对较新，它还没有得到充分的表征。迄今为止，最大（n = 43）患者队列的深度表型确定肌张力减退和先天性心脏缺陷是以前与该综合征无关的突出特征。错义变体和推定的功能丧失变体都导致患者来源的细胞系生长缓慢。KMT5B纯合子基因敲除小鼠的体型小于其野生型同窝出生的小鼠，但大脑并不显著较小，这表明相对的大头畸形，也被认为是一个突出的临床特征。患者淋巴母细胞和Kmt5b单倍不足小鼠脑的RNA测序鉴定了与神经系统发育和功能相关的差异表达途径，包括轴突导向信号传导。总体而言，我们确定了KMT5B相关神经发育障碍的其他致病变异和临床特征，并使用多个模型系统深入了解了该疾病的分子机制。KMT5B的缺失导致细胞增殖减少和对神经发育重要的基因的差异调节。
Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems. Loss of KMT5B results in decreased cellular proliferation and differential regulation of genes important for neurodevelopment.
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影响因子：
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影响因子：
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DOI：
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发表时间：
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