TY - JOUR
T1 - Extensive phenotyping of two ARX polyalanine expansion mutation mouse models that span clinical spectrum of intellectual disability and epilepsy
AU - Jackson, Matilda R.
AU - Lee, Kristie
AU - Mattiske, Tessa
AU - Jaehne, Emily J.
AU - Ozturk, Ezgi
AU - Baune, Bernhard T.
AU - O'Brien, Terence J.
AU - Jones, Nigel
AU - Shoubridge, Cheryl
PY - 2017/9/1
Y1 - 2017/9/1
N2 - The Aristaless-related homeobox gene (ARX) is a known intellectual disability (ID) gene that frequently presents with X-linked infantile spasm syndrome as a comorbidity. ID with epilepsy in children is a chronic and devastating disorder that has poor treatment options and disease outcomes. To gain a better understanding of the role that mutations in ARX play in ID and epilepsy, we investigate ARX patient mutations modelled in mice. Over half of all ARX mutations result from expansions of the first two polyalanine (PA1 and PA2 respectively) tracts. However, phenotypic data for the mouse modelling the more frequent ARX PA2 dup24 mutation in patients has not been reported and constitutes a barrier to understanding the molecular mechanisms involved. Here we report the first comprehensive analysis of postnatal outcomes for mice modelling disease-causing expansions to both PA1 and PA2 tracts. Both strains were found to have impaired learning and memory, reduced activity, increased anxiety and reduced sociability; with PA1 mice generally displaying greater behavioural deficits in keeping with the more severe phenotype reported in patients. In agreement with previous reports, 70% of PA1 males exhibit myoclonic seizures by two months of age, with the first observed at P18. In this report, we show 80% of PA2 males also display myoclonic seizures, with the first observed at P19. Consistent with patient phenotypes, we observe large variations in seizure progression and severity for both PA1 and PA2 individual mice. The generation of this comprehensive baseline data is a necessary step on the path to the development of therapies to improve patient outcomes.
AB - The Aristaless-related homeobox gene (ARX) is a known intellectual disability (ID) gene that frequently presents with X-linked infantile spasm syndrome as a comorbidity. ID with epilepsy in children is a chronic and devastating disorder that has poor treatment options and disease outcomes. To gain a better understanding of the role that mutations in ARX play in ID and epilepsy, we investigate ARX patient mutations modelled in mice. Over half of all ARX mutations result from expansions of the first two polyalanine (PA1 and PA2 respectively) tracts. However, phenotypic data for the mouse modelling the more frequent ARX PA2 dup24 mutation in patients has not been reported and constitutes a barrier to understanding the molecular mechanisms involved. Here we report the first comprehensive analysis of postnatal outcomes for mice modelling disease-causing expansions to both PA1 and PA2 tracts. Both strains were found to have impaired learning and memory, reduced activity, increased anxiety and reduced sociability; with PA1 mice generally displaying greater behavioural deficits in keeping with the more severe phenotype reported in patients. In agreement with previous reports, 70% of PA1 males exhibit myoclonic seizures by two months of age, with the first observed at P18. In this report, we show 80% of PA2 males also display myoclonic seizures, with the first observed at P19. Consistent with patient phenotypes, we observe large variations in seizure progression and severity for both PA1 and PA2 individual mice. The generation of this comprehensive baseline data is a necessary step on the path to the development of therapies to improve patient outcomes.
KW - Aristaless-related homeobox gene
KW - Intellectual disability
KW - ISSX
KW - Polyalanine tract expansion
KW - Seizure phenotype
UR - http://www.scopus.com/inward/record.url?scp=85020864032&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2017.05.012
DO - 10.1016/j.nbd.2017.05.012
M3 - Article
AN - SCOPUS:85020864032
VL - 105
SP - 245
EP - 256
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -