Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
复制标题
DOI：
10.1016/j.ajhg.2018.02.021
复制
发表时间：
2018-05-03
影响因子：
9.8
通讯作者：
Kury, Sebastien
中科院分区：
文献类型：
--
作者：
Guissart, Claire;Latypova, Xenia;Kury, Sebastien
ROR α是与RAR相关的孤儿核受体α，对于小脑发育至关重要。自发突变小鼠蹒跚，与共济失调步态所造成的小脑浦肯野细胞的神经变性，被发现二十年前纯合子基因内Rora缺失。然而，RORA突变迄今为止在人类中没有记录。通过多中心合作，我们确定了三个拷贝数变异缺失（两个从头突变和一个显性遗传三代），一个从头突变破坏重复，和九个从头点突变（三个截短，一个典型剪接位点，和五个错义突变）涉及来自13个家族的16个个体的RORA，这些个体具有可变的神经发育迟缓和智力残疾（ID）相关的自闭症特征，小脑共济失调和癫痫与人类和小鼠的数据一致，D. rerio直系同源物roraa导致发育中的小脑尺寸显著减小。系统的体内互补研究表明，而野生型人RORA mRNA可以补充小脑病理，错义变体有两种不同的致病机制，根据其定位在配体结合或DNA结合域，分别为单倍不足或显性毒性作用。这种效应的二分方向可能与人类的表型相关：具有导致单倍性不足的功能丧失变体的个体显示具有自闭症特征的ID，而具有从头显性毒性变体的个体呈现ID、共济失调和小脑萎缩。我们结合的遗传和功能数据突出了人类RORA基因座复杂的突变景观，并表明双重突变效应可能决定表型结果。
ROR alpha, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, mis sense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.