Abstract
Paroxysmal kinesigenic dyskinesia (PKD) is an episodic movement disorder with autosomal-dominant inheritance and marked variability in clinical manifestations.Proline-rich transmembrane protein 2 (PRRT2) has been identified as a causative gene of PKD, but the molecular mechanism underlying the pathogenesis of PKD still remains a mystery. The phenotypes and transcriptional patterns of the PKD disease need further clarification. Here, we report the generation and neural differentiation of iPSC lines from two familial PKD patients with c.487C>T (p. Gln163X) and c.573dupT (p. Gly192Trpfs*8) PRRT2 mutations, respectively. Notably, an extremely lower efficiency in neural conversion from PKD-iPSCs than control-iPSCs is observed by a step-wise neural differentiation method of dual inhibition of SMAD signaling. Moreover, we show the high expression level of PRRT2 throughout the human brain and the expression pattern of PRRT2 in other human tissues for the first time. To gain molecular insight into the development of the disease, we conduct global gene expression profiling of PKD cells at four different stages of neural induction and identify altered gene expression patterns, which peculiarly reflect dysregulated neural transcriptome signatures and a differentiation tendency to mesodermal development, in comparison to control-iPSCs. Additionally, functional and signaling pathway analyses indicate significantly different cell fate determination between PKD-iPSCs and control-iPSCs. Together, the establishment of PKD-specific in vitro models and the illustration of transcriptome features in PKD cells would certainly help us with better understanding of the defects in neural conversion as well as further investigations in the pathogenesis of the PKD disease.
Highlights
Paroxysmal kinesigenic dyskinesia (PKD) was initially described in 1967 and is recognized as the most common type of paroxysmal movement disorder [1,2,3]
Previous study has reported that PRRT2 was identified as the pathogenesis-associated gene of PKD, and it was highly expressed in the mouse brain and spinal cord, displaying a dynamic expression pattern during mouse development [11]
We focus on the detailed differences of cell phenotype and transcriptional expression profiles between PKD-induced pluripotent stem cell (iPSC) and normal iPSCs during the relatively early phases of neural differentiation, which could be captured through the step-wise neural induction method by dual inhibition of SMAD signaling
Summary
Paroxysmal kinesigenic dyskinesia (PKD) was initially described in 1967 and is recognized as the most common type of paroxysmal movement disorder [1,2,3]. By combining classic linkage analysis with wholeexome sequencing, mutations in the PRRT2 gene have been identified as the cause of PKD [11]. This result was rapidly supported by other reports performed in families from different ethnic backgrounds with PKD [12,13,14,15,16]. PRRT2 mutations were discovered in Infantile Convulsions and Choreoathetosis (ICCA) [15, 17] and Benign Familial Infantile Epilepsy (BFIE) [15, 18, 19]. PRRT2 mutations have been described in over 330 families from different ethnic backgrounds with PKD, BFIE and ICCA [20, 21]. Several of the mutations have been demonstrated to cause altered cellular localization of PRRT2 proteins [17, 20]
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