Abstract
BackgroundA spontaneous de novo mutation is a new mutation appeared in a child that neither the parent carries. Recent studies suggest that recurrent de novo loss-of-function mutations identified in patients with sporadic autism spectrum disorder (ASD) play a key role in the etiology of the disorder. POGZ is one of the most recurrently mutated genes in ASD patients. Our laboratory and other groups have recently found that POGZ has at least 18 independent de novo possible loss-of-function mutations. Despite the apparent importance, these mutations have never previously been assessed via functional analysis.MethodsUsing wild-type, the Q1042R-mutated, and R1008X-mutated POGZ, we performed DNA-binding experiments for proteins that used the CENP-B box sequence in vitro. Data were statistically analyzed by one-way ANOVA followed by Tukey-Kramer post hoc tests.ResultsThis study reveals that ASD-associated de novo mutations (Q1042R and R1008X) in the POGZ disrupt its DNA-binding activity.ConclusionsHere, we report the first functional characterization of de novo POGZ mutations identified in sporadic ASD cases. These findings provide important insights into the cellular basis of ASD.
Highlights
A spontaneous de novo mutation is a new mutation appeared in a child that neither the parent carries
The Q1042R mutation was associated with a reduction of approximately 60 % in DNA-binding, suggesting that Q1042 is important for the DNA-binding activity of POGZ (Fig. 2b)
We examined the DNA-binding activity of POGZ carrying the autism spectrum disorder (ASD)-associated R1008X de novo mutation; this mutation results in a truncated protein that lacks the entire CENPB-DB domain
Summary
A spontaneous de novo mutation is a new mutation appeared in a child that neither the parent carries. Recent studies suggest that recurrent de novo loss-of-function mutations identified in patients with sporadic autism spectrum disorder (ASD) play a key role in the etiology of the disorder. POGZ is one of the most recurrently mutated genes in ASD patients. Our laboratory and other groups have recently found that POGZ has at least 18 independent de novo possible loss-of-function mutations. Recent next-generation sequencing studies have demonstrated that de novo mutations greatly contribute to the risk of ASD and often produce large effects [1,2,3,4,5]. Genes with highly recurrent de novo possible loss-of-function mutations play key roles in the etiology of this disorder. De novo mutations in multiple (≥3) unrelated patients have been identified in several such high-confidence ASD risk genes, Matsumura et al Journal of Molecular Psychiatry (2016) 4:1. Neuron immunocytochemistry (at 7 days in vitro) was performed as previously described [13]
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