Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome.
Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome.
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DOI：
10.1172/jci.insight.167074
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发表时间：
2023-05-08
期刊：
影响因子：
8
通讯作者：
Baron, Jeffrey
中科院分区：
文献类型：
--
作者：
Lui, Julian C.;Wagner, Jacob;Zhou, Elaine;Dong, Lijin;Barnes, Kevin M.;Jee, Youn Hee;Baron, Jeffrey
过度生长综合征可由表观遗传学中的致病性遗传变异引起，如DNA和组蛋白甲基转移酶。然而，没有过度生长障碍以前已被归因于变异的基因，主要作为一个表观遗传读者。在这里，我们研究了一个男性个体与产前发病的全身性过度生长。外显子组测序鉴定了Spindlin 4（SPIN 4）中的半合子移码变体，具有X连锁遗传。我们发现SPIN 4结合特异性组蛋白修饰，促进经典WNT信号传导，并抑制体外细胞增殖的证据，并且鉴定的移码变体已经失去了所有这些功能。在小鼠中消融Spin4重现了具有全身性过度生长的人类表型，包括纵向骨生长增加。生长板分析显示增殖区的细胞增殖增加，静止区的祖软骨细胞数量增加。我们还发现了生长板软骨细胞中典型Wnt信号减少的证据，为静息区软骨细胞数量增加提供了一个潜在的解释。总之，我们的研究结果提供了强有力的证据，证明SPIN 4是一种表观遗传阅读器，负调控哺乳动物的身体生长，SPIN 4的缺失会导致人类过度生长综合征，扩大了我们对人类生长的表观遗传调控的认识。
Overgrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has previously been ascribed to variants in a gene that acts primarily as an epigenetic reader. Here, we studied a male individual with generalized overgrowth of prenatal onset. Exome sequencing identified a hemizygous frameshift variant in Spindlin 4 (SPIN4), with X-linked inheritance. We found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, and inhibits cell proliferation in vitro and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes. Taken together, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth.
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影响因子：
16.6
作者：
Lui JC;Raimann A;Hojo H;Dong L;Roschger P;Kikani B;Wintergerst U;Fratzl-Zelman N;Jee YH;Haeusler G;Baron J
通讯作者：
Baron J
DOI：
10.1038/s41436-020-0803-8
发表时间：
2020-08
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Jee YH;Won S;Lui JC;Jennings M;Whalen P;Yue S;Temnycky AG;Barnes KM;Cheetham T;Boden MG;Radovick S;Quinton R;Leschek EW;Aguilera G;Yanovski JA;Seminara SB;Crowley WF;Delaney A;Roche KW;Baron J
通讯作者：
Baron J
影响因子：
3.9
作者：
Shanle EK;Shinsky SA;Bridgers JB;Bae N;Sagum C;Krajewski K;Rothbart SB;Bedford MT;Strahl BD
通讯作者：
Strahl BD
影响因子：
4.1
作者：
Lui JC;Yue S;Lee A;Kikani B;Temnycky A;Barnes KM;Baron J
通讯作者：
Baron J
影响因子：
8
作者：
De Pauw, Aurelia;Andre, Emilie;Balligand, Jean-Luc
通讯作者：
Balligand, Jean-Luc