A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.
A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.
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复发性DE NOVO MAX P.ARG60GLN变体通过C-MYC靶基因的差异表达引起综合性过度生长障碍。
DOI：
10.1016/j.ajhg.2023.11.010
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发表时间：
2024-01-04
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞周期蛋白D2(CCND2)的稳定性通过CCND2的突变或激活编码PI3K-AKT通路组件的上游基因的突变来支持一系列与大头畸形相关的疾病。在这里，我们描述了三个具有重叠的大头畸形相关表型的个体，他们携带着Myc相关因子X(Max)的相同的重复性新发基因C.179G和gt；A(p.Arg60Gln)变异。该突变位于b-HLH-LZ结构域，通过增加转录导致细胞内CCND2增加，但不会导致CCND2的稳定。我们发现，纯化的MAXArg60Gln(Max∗Arg60Gln)的b-hlh-LZ结构域与其目标E-box序列具有较低的表观亲和力。这导致了与c-Myc更有效的异源二聚化，导致携带该突变的个体c-Myc转录活性增加。Oomomyc-CPP是一种细胞穿透性b-HLH-LZ结构域c-Myc抑制剂，最近的研究为MAXArg60Gln个体和其他携带类似胚系突变导致c-Myc活性异常的人提供了一种可能的治疗选择。Harris等人。描述三个具有重叠的大头畸形相关表型的个体，携带Myc相关因子X(Max)中的一个重复的新发C.179G>；A(p.Arg60Gln)变异。MAXArg60Gln以较低的亲和力结合其目标E-box序列，这意味着更有效地与c-Myc和转录活性失调的异源二聚。C-Myc抑制剂为携带这种变异体的个体提供了一种可能的治疗选择。
Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity. Harris et al. describe three individuals with overlapping macrocephaly-associated phenotypes carrying a recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). MAXArg60Gln binds its target E-box sequence with a lower affinity, meaning more efficient heterodimerization with c-Myc and dysregulated transcriptional activity. c-Myc inhibitors provide a possible therapeutic option for individuals carrying this variant.
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