Santiago-Sim Teresa, Burrage Lindsay C, Ebstein Frédéric, Tokita Mari J, Miller Marcus, Bi Weimin, Braxton Alicia A, Rosenfeld Jill A, Shahrour Maher, Lehmann Andrea, Cogné Benjamin, Küry Sébastien, Besnard Thomas, Isidor Bertrand, Bézieau Stéphane, Hazart Isabelle, Nagakura Honey, Immken LaDonna L, Littlejohn Rebecca O, Roeder Elizabeth, Kara Bulent, Hardies Katia, Weckhuysen Sarah, May Patrick, Lemke Johannes R, Elpeleg Orly, Abu-Libdeh Bassam, James Kiely N, Silhavy Jennifer L, Issa Mahmoud Y, Zaki Maha S, Gleeson Joseph G, Seavitt John R, Dickinson Mary E, Ljungberg M Cecilia, Wells Sara, Johnson Sara J, Teboul Lydia, Eng Christine M, Yang Yaping, Kloetzel Peter-Michael, Heaney Jason D, Walkiewicz Magdalena A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Am J Hum Genet. 2017 Apr 6;100(4):676-688. doi: 10.1016/j.ajhg.2017.03.001. Epub 2017 Mar 23.
Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.
泛素化是一种翻译后修饰，可调节许多细胞过程，包括蛋白质降解、细胞内运输、细胞信号传导以及蛋白质-蛋白质相互作用。去泛素化酶（DUBs）可逆转泛素化过程，是泛素系统的重要调节因子。OTUD6B编码去泛素化酶中含卵巢肿瘤结构域（OTU）亚家族的一个成员。在此，我们报告了来自6个独立家庭的12名个体中OTUD6B的双等位基因致病变异，这些个体患有与癫痫发作和畸形特征相关的智力残疾综合征。在具有预测功能丧失等位基因的受试者中，其他特征包括全面发育迟缓、小头畸形、无言语能力、肌张力减退、产前开始的生长发育迟缓、喂养困难、脑结构异常、包括先天性心脏病在内的先天性畸形以及肌肉骨骼特征。纯合Otud6b基因敲除小鼠存活能力差、体型较小且患有先天性心脏缺陷，这与人类功能丧失变异的严重程度一致。对一名受影响受试者的外周血单核细胞分析显示，19S亚基掺入26S蛋白酶体的量减少、类胰凝乳蛋白酶样活性降低以及泛素-蛋白质缀合物积累。我们的研究结果表明OTUD6B在蛋白酶体功能中起作用，证实有缺陷的OTUD6B功能是一种多系统人类疾病的基础，并为泛素系统与人类疾病之间新出现的关系提供了更多证据。
