Age-dependent neurological phenotypes in a mouse model of PRRT2-related diseases

Fay Aj,Li H,Niesner Kj,Nelson A,Bair-Marshall C,Ptáček Lj,Voglmaier Sm,Fu Y-H,Im C,Mcmahon T

doi:10.1007/s10048-021-00645-6

Abstract

Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.

Highlights

Mutations in the proline-rich transmembrane protein PRRT2 were implicated in several paroxysmal neurological disorders almost a decade ago,[1,2,3,4,5] and over the past several years, a more detailed understanding of the functions of this protein has emerged
A unique and poorly understood feature of PRRT2-related diseases is the age dependence of the various phenotypes: seizures tend to occur in the infantile period [14] and abate within the first 2 years, whereas paroxysmal kinesigenic dyskinesia typically appears among school-age children, and may continue through mid-adulthood, after which time it often improves
Efforts of several groups have helped to elucidate the mechanisms of PRRT2 mutations in synaptic function, through a combination of knockdown [8, 9, 28] and knockout [5, 9, 14,15,16] approaches in rodent models, along with immunohistochemistry, electrophysiology, and behavioral experiments

Summary

Introduction

Mutations in the proline-rich transmembrane protein PRRT2 were implicated in several paroxysmal neurological disorders almost a decade ago,[1,2,3,4,5] and over the past several years, a more detailed understanding of the functions of this protein has emerged. PRRT2-related disorders include dominant paroxysmal kinesigenic dyskinesia [6] and benign familial infantile seizures, with rare manifestations of episodic ataxia and hemiplegic migraine. [7, 8] In addition, a small number of patients have been identified who carry biallelic mutations in PRRT2, resulting in a more severe phenotype that includes intellectual disability, developmental delay, ataxia, and paroxysmal dyskinesias. A unique and poorly understood feature of PRRT2-related diseases is the age dependence of the various phenotypes: seizures tend to occur in the infantile period [14] and abate within the first 2 years, whereas paroxysmal kinesigenic dyskinesia typically appears among school-age children, and may continue through mid-adulthood, after which time it often improves. We explore the effects of PRRT2 heterozygous and knockout states in mice, including the age-dependent expression of synaptic proteins and motor manifestations

Methods

Results

Conclusion