KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.
KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.
复制标题
DOI：
10.1038/nature11091
复制
发表时间：
2012-05-16
期刊：
影响因子：
64.8
通讯作者：
Katsanis, Nicholas
中科院分区：
文献类型：
--
作者：
Golzio, Christelle;Willer, Jason;Talkowski, Michael E.;Oh, Edwin C.;Taniguchi, Yu;Jacquemont, Sebastien;Reymond, Alexandre;Sun, Mei;Sawa, Akira;Gusella, James F.;Kamiya, Atsushi;Beckmann, Jacques S.;Katsanis, Nicholas
拷贝数变异（CNVs）是遗传性疾病的主要贡献者。我们已经解剖了16p11.2染色体的一个区域，它包含29个基因，当缺失或重复时，它赋予神经认知缺陷的易感性。在斑马鱼胚胎中，每种人类转录本的过表达鉴定出KCTD 13是能够诱导与16p11.2重复相关的小头畸形表型的唯一信息，，，，而抑制相同位点产生与16p11.2缺失相关的大头畸形表型，，捕获人类的镜像表型。对斑马鱼和小鼠胚胎的分析表明，小头畸形是由神经元祖细胞增殖减少引起的，伴随着发育中的脑细胞凋亡的增加，而大头畸形是由增殖增加而细胞凋亡没有变化引起的。KCTD 13剂量变化的作用与最近报道的一个16p11.2缺失减少的家族和一个复杂的16p11.2重排涉及KCTD 13的新结构改变的受试者的自闭症一致。我们的数据表明KCTD 13是与16p11.2 CNV相关的神经发育表型的主要驱动因素，加强了CNV中一个或少量转录本可以支持临床表型的观点，并提供了一种有效的途径来识别剂量敏感位点。
Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome—which encompasses 29 genes—that confers susceptibility to neurocognitive defects when deleted or duplicated,. Overexpression of each human transcript in zebrafish embryos identifiedKCTD13as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication,,,, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion,, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role forKCTD13dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involvingde novostructural alteration ofKCTD13. Our data suggest thatKCTD13is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.
登录
查看更多内容
影响因子：
158.5
作者：
ROA, BB;GARCIA, CA;LUPSKI, JR
通讯作者：
LUPSKI, JR
影响因子：
30.8
作者：
McCarthy, Shane E.;Makarov, Vladimir;Kirov, George;Addington, Anjene M.;McClellan, Jon;Yoon, Seungtai;Perkins, Diana O.;Dickel, Diane E.;Kusenda, Mary;Krastoshevsky, Olga;Krause, Verena;Kumar, Ravinesh A.;Grozeva, Detelina;Malhotra, Dheeraj;Walsh, Tom;Zackai, Elaine H.;Kaplan, Paige;Ganesh, Jaya;Krantz, Ian D.;Spinner, Nancy B.;Roccanova, Patricia;Bhandari, Abhishek;Pavon, Kevin;Lakshmi, B.;Leotta, Anthony;Kendall, Jude;Lee, Yoon-ha;Vacic, Vladimir;Gary, Sydney;Iakoucheva, Lilia M.;Crow, Timothy J.;Christian, Susan L.;Lieberman, Jeffrey A.;Stroup, T. Scott;Lehtimaki, Terho;Puura, Kaija;Haldeman-Englert, Chad;Pearl, Justin;Goodell, Meredith;Willour, Virginia L.;DeRosse, Pamela;Steele, Jo;Kassem, Layla;Wolff, Jessica;Chitkara, Nisha;McMahon, Francis J.;Malhotra, Anil K.;Potash, James B.;Schulze, Thomas G.;Noethen, Markus M.;Cichon, Sven;Rietschel, Marcella;Leibenluft, Ellen;Kustanovich, Vlad;Lajonchere, Clara M.;Sutcliffe, James S.;Skuse, David;Gill, Michael;Gallagher, Louise;Mendell, Nancy R.;Craddock, Nick;Owen, Michael J.;O'Donovan, Michael C.;Shaikh, Tamim H.;Susser, Ezra;DeLisi, Lynn E.;Sullivan, Patrick F.;Deutsch, Curtis K.;Rapoport, Judith;Levy, Deborah L.;King, Mary-Claire;Sebat, Jonathan
通讯作者：
Sebat, Jonathan
影响因子：
158.5
作者：
Weiss, Lauren A.;Shen, Yiping;Daly, Mark J.
通讯作者：
Daly, Mark J.
自闭症中发现的 16p11.2 病变模型的剂量依赖性表型
DOI：
10.1073/pnas.1114042108
发表时间：
2011-10-11
影响因子：
11.1
作者：
Horev, Guy;Ellegood, Jacob;Mills, Alea A.
通讯作者：
Mills, Alea A.
影响因子：
64.8
作者：
Jacquemont, Sebastien;Reymond, Alexandre;Froguel, Philippe
通讯作者：
Froguel, Philippe