Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features
Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features
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DOI：
10.1186/s13229-019-0271-7
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发表时间：
2019-05-03
期刊：
影响因子：
6.2
通讯作者：
Godler, David E.
中科院分区：
文献类型：
--
作者：
Baker, Emma K.;Arpone, Marta;Godler, David E.
脆性X综合征（Fragile X syndrome，FXS）是一种常见的单基因遗传性的具有孤独症特征的智力残疾.虽然它是由FMR 1产物（FMRP）的丢失引起的，但活性和非活性FMR 1等位基因的嵌合现象，包括称为前突变（PM：55-199 CGG）的等位基因，并不罕见。重要的是，PM和活性完全突变（FM：200 CGGs）等位基因通常表达被认为是有毒的mRNA水平升高。本研究确定，如果完全FMR 1基因沉默从FM等位基因和/或FMR 1基因（如果存在）在血液中的水平与智力功能和自闭症功能在FXS.MethodsThe研究队列包括98名参与者（70.4%男性）与FXS（FM-唯一和PM/FM马赛克）年龄1- 43岁。使用14只雌性动物的对照组建立对照FMR 1 mRNA参考范围。智力功能和自闭症特征分别使用马伦早期学习量表或适合年龄的韦氏量表和自闭症诊断观察表-第2版（ADOS-2）进行评估。FMR 1 mRNA在静脉血中进行了分析，在评估时收集，使用实时PCR相对标准曲线法。
BackgroundFragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the FMR1 product (FMRP), mosaicism for active and inactive FMR1 alleles, including alleles termed premutation (PM: 55-199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: 200CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete FMR1 mRNA silencing from FM alleles and/or levels of FMR1 mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS.MethodsThe study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1-43years. A control group of 14 females were used to establish control FMR1 mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively. FMR1 mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method.ResultsFemales with FXS had significantly higher levels of FMR1 mRNA (p