CUL4B基因丧失功能突变的病理机制及临床意义

doi:10.6040/j.issn.1671-7554.0.2026.1016

摘要/Abstract

摘要： CUL4B基因的丧失功能突变是X连锁智力低下(X-linked mental retardation, XLMR)综合征最常见的致病基因之一。患者除智力低下外还伴有语言发育迟缓、运动发育迟缓、癫痫、身材矮小、短指、肥胖、外周血中单核细胞增多、性腺功能减退等症状,提示CUL4B基因在多种组织器官的发育和稳态维持中发挥广泛作用。解析CUL4B基因丧失功能突变导致以上症状的致病机制,不仅有助于理解该基因的功能,而且可以为该疾病及其相关疾病的治疗提供新的思路。本文围绕CUL4B基因丧失功能突变在智力低下、癫痫、代谢、骨骼及免疫等方面的病理机制和临床意义展开论述。

关键词: CUL4B基因, 智力低下, 癫痫, 骨骼, 免疫

Abstract: The loss-of-function mutation of CUL4B gene is one of the most common pathogenic genes in X-linked mental retardation(XLMR)syndrome. In addition to intellectual disability, patients also have symptoms such as speech delay, motor delay, seizures, short stature, brachydactyly, obesity, increased monocyte counts in peripheral blood, and hypogonadism, indicating that the CUL4B gene plays a broad role in the development and homeostasis maintenance of various tissues and organs. Analyzing the pathogenic mechanisms of CUL4B gene loss-of-function mutations leading to the above symptoms not only helps to understand the function of this gene, but also provides new insights for the treatment of this disease and related diseases. This article will discuss the pathological mechanisms and clinical significances of CUL4B gene loss-of-function mutations in areas such as intellectual disability, epilepsy, metabolism, skeleton, and immunity.

Key words: CUL4B gene, Intellectual disability, Epilepsy, Skeleton, Immunity

中图分类号:

Q343.1

蒋百春,龚瑶琴. CUL4B基因丧失功能突变的病理机制及临床意义[J]. 山东大学学报 (医学版), 2026, 64(10): 88-94.

JIANG Baichun, GONG Yaoqin. Pathological mechanisms and clinical significances of CUL4B gene loss-of-function mutations[J]. Journal of Shandong University (Health Sciences), 2026, 64(10): 88-94.

参考文献

[1] Tarpey P S, Raymond F L, OMeara S, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor [J]. Am J Hum Genet, 2007, 80(2): 345-352.
[2] Zou Y, Liu Q, Chen B, et al. Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation [J]. Am J Hum Genet, 2007, 80(3): 561-566.
[3] Tarpey P S, Smith R, Pleasance E, et al. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation [J]. Nat Genet, 2009, 41(5): 535-543.
[4] Jackson S, Xiong Y. CRL4s: the CUL4-RING E3 ubi-quitin ligases [J]. Trends Biochem Sci, 2009, 34(11):562-570.
[5] Hu H, Yang Y, Ji Q, et al. CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis [J]. Cancer Cell, 2012, 22(6): 781-795.
[6] Chen C Y, Tsai M S, Lin C Y, et al. Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation [J]. Hum Mol Genet, 2012, 21(19): 4270-4285.
[7] Jiang W, Zhang J, Wang M, et al. The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function [J]. Acta Neuropathol Commun, 2024, 12(1): 188. DOI: 10.1186/s40478-024-01903-y
[8] Zhao W, Jiang B, Hu H, et al. Lack of CUL4B leads to increased abundance of GFAP-positive cells that is mediated by PTGDS in mouse brain [J]. Hum Mol Genet, 2015, 24(16): 4686-4697.
[9] Di Lullo E, Kriegstein A R. The use of brain organoids to investigate neural development and disease [J]. Nat Rev Neurosci, 2017, 18(10): 573-584.
[10] Liu X, Yang X, Li Y, et al. Generation of patient-specific pluripotent induced stem cell line SDUBMSI002-A from a patient with X-linked mental retardation syndrome [J]. Stem Cell Res, 2020, 43: 101724. DOI: 10.1016/j.scr.2020.101724
[11] Guan J, Liu X, Zhang H, et al. Generation of an iPSC line(SDQLCHi015-A)from peripheral blood mononuclear cells of a patient with mental retardation type 15 carrying c.1007_1011del, p.(Ile336fs)in CUL4B gene [J]. Stem Cell Res, 2019, 41: 101628. DOI: 10.1016/j.scr.2019.101628
[12] Ma Y, Liu X, Zhou M, et al. CUL4B mutations impair human cortical neurogenesis through PP2A-dependent inhibition of AKT and ERK [J]. Cell Death Dis, 2024, 15(2): 121. DOI: 10.1038/s41419-024-06501-3
[13] Della Vecchia S, Lopergolo D, Trovato R, et al. CUL4B-associated epilepsy: report of a novel truncating variant promoting drug-resistant seizures and systematic review of the literature [J]. Seizure, 2023, 104:32-37.DOI: 10.1016/j.seizure.2022.11.014
[14] Jiang W, Ma Y Y, Wang Y F, et al. GABA transporter 1 is a promising drug target for CUL4B mutation-associated epilepsy [J]. Acta Pharmacol Sin, 2025, 46(6): 1580-1591.
[15] Li P, Song Y, Zan W, et al. Lack of CUL4B in adipocytes promotes PPARγ-mediated adipose tissue expansion and insulin sensitivity [J]. Diabetes, 2017, 66(2): 300-313.
[16] Dou H, Duan Y, Zhang X, et al. Aryl hydrocarbon receptor(AhR)regulates adipocyte differentiation by assembling CRL4B ubiquitin ligase to target PPARγ-amma for proteasomal degradation [J]. J Biol Chem, 2019, 294(48): 18504-18515.
[17] Yu R, Han H, Chu S, et al. CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPdelta [J]. Bone Res, 2023, 11(1): 29. DOI: 10.1038/s41413-023-00263-y
[18] Hung M H, Jian Y R, Tsao C C, et al. Enhanced LPS-induced peritonitis in mice deficiency of cullin 4B in macrophages [J]. Genes Immun, 2014, 15(6): 404-412.
[19] Zong Y, Shan H, Yin F, et al. Ddb1-Cullin4-associated-factor 1 in macrophages restricts the staphylococcus aureus-induced osteomyelitis[J]. J Inflamm Res, 2021, 14: 1667-1676. DOI: 10.2147/JIR.S307316
[20] Song Y, Li P, Qin L, et al. CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription [J]. Cell Mol Immunol, 2021, 18(2): 339-349.
[21] Jin S, Song Y, Zhou L, et al. Depletion of CUL4B in macrophages ameliorates diabetic kidney disease via miR-194-5p/ITGA9 axis [J]. Cell Rep, 2023, 42(6): 112550. DOI: 10.1016/j.celrep.2023.112550
[22] Dar A A, Sawada K, Dybas J M, et al. The E3 ubiqui-tin ligase Cul4b promotes CD4⁺ T cell expansion by aiding the repair of damaged DNA [J]. PLoS Biol, 2021, 19(2): e3001041. DOI: 10.1371/journal.pbio.3001041
[23] Yang L, Chen W, Li L, et al. Ddb1 is essential for the expansion of CD4(+)helper T cells by regulating cell cycle progression and cell death [J]. Front Immunol, 2021, 12: 722273. DOI: 10.3389/fimmu.2021.722273
[24] Qin L, Song Y, Zhang F, et al. CRL4B complex-mediated H2AK119 monoubiquitination restrains Th1 and Th2 cell differentiation [J]. Cell Death Differ, 2023, 30(6): 1488-1502.
[25] Qian Y, Yuan J, Hu H, et al. The CUL4B/AKT/beta-catenin axis restricts the accumulation of myeloid-derived suppressor cells to prohibit the establishment of a tumor-permissive microenvironment [J]. Cancer Res, 2015, 75(23): 5070-5083.
[26] Xu Z, Li L, Qian Y, et al. Upregulation of IL-6 in CUL4B-deficient myeloid-derived suppressive cells increases the aggressiveness of cancer cells [J]. Oncogene, 2019, 38(30): 5860-5872.

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