Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.
Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.
复制标题
DOI：
10.1038/s41436-021-01152-7
复制
发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Schaaf CP
中科院分区：
文献类型：
--
作者：
Marbach F;Stoyanov G;Erger F;Stratakis CA;Settas N;London E;Rosenfeld JA;Torti E;Haldeman-Englert C;Sklirou E;Kessler E;Ceulemans S;Nelson SF;Martinez-Agosto JA;Palmer CGS;Signer RH;Undiagnosed Diseases Network;Andrews MV;Grange DK;Willaert R;Person R;Telegrafi A;Sievers A;Laugsch M;Theiß S;Cheng Y;Lichtarge O;Katsonis P;Stocco A;Schaaf CP
我们描述了6名患有智力残疾和自闭症谱系障碍的无关个体的临床和分子表型，这些个体携带PRKAR1B基因的杂合错义变体，该基因编码环AMP依赖性蛋白激酶A（PKA）的R1 β亚基。通过单外显子组或三外显子组分析鉴定PRKAR1B的变体。我们联系了这六个人的家庭和医生，收集表型信息，对识别出的PRKAR1B变体进行体外分析，并研究了胚胎发育过程中PRKAR1B的表达。最近对患有神经发育障碍的大型患者队列的研究发现PRKAR1B中的从头错义变体显著富集。在我们的队列中，可以在6个个体中的5个中证实PRKAR1B变体的从头起源，并且4个携带相同的杂合从头变体c.1003C> T（p.Arg335Trp; NM_001164760）。在所有六个人中都报告了全面发育迟缓，自闭症谱系障碍和失用症/运动障碍，并且在三个携带c.1003C> T变体的个体中发现了疼痛敏感性降低。PRKAR1B在人类胚胎发育过程中在大脑中的表达得到证实。此外，体外分析显示，在用携带PRKAR1B表达构建体的变体转染的细胞中，基础PKA活性改变。我们的研究为PRKAR1B相关的神经发育障碍提供了强有力的证据。
We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
登录
查看更多内容
影响因子：
16.2
作者：
CADD, G;MCKNIGHT, GS
通讯作者：
MCKNIGHT, GS
影响因子：
30.8
作者：
Coe, Bradley P.;Stessman, Holly A. F.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
影响因子：
7.7
作者：
Ilouz, Ronit;Lev-Ram, Varda;Taylor, Susan S.
通讯作者：
Taylor, Susan S.
影响因子：
23.9
作者：
Laugsch, Magdalena;Bartusel, Michaela;Rada-Iglesias, Alvaro
通讯作者：
Rada-Iglesias, Alvaro
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G