Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females.
Mutations in the X-linked aristaless-related homeobox gene (ARX) have been linked to structural brain anomalies as well as multiple neurocognitive deficits. The generation of Arx-deficient mice revealed several morphological anomalies, resembling those observed in patients and an interneuron migration defect but perinatal lethality precluded analyses of later phenotypes. Interestingly, many of the neurological phenotypes observed in patients with various ARX mutations can be attributed, in part, to interneuron dysfunction. To directly test this possibility, mice carrying a floxed Arx allele were generated and crossed to Dlx5/6(CRE-IRES-GFP)(Dlx5/6(CIG)) mice, conditionally deleting Arx from ganglionic eminence derived neurons including cortical interneurons. We now report that Arx(-/y);Dlx5/6(CIG) (male) mice exhibit a variety of seizure types beginning in early-life, including seizures that behaviourally and electroencephalographically resembles infantile spasms, and show evolution through development. Thus, this represents a new genetic model of a malignant form of paediatric epilepsy, with some characteristics resembling infantile spasms, caused by mutations in a known infantile spasms gene. Unexpectedly, approximately half of the female mice carrying a single mutant Arx allele (Arx(-/+);Dlx5/6(CIG)) also developed seizures. We also found that a subset of human female carriers have seizures and neurocognitive deficits. In summary, we have identified a previously unrecognized patient population with neurological deficits attributed to ARX mutations that are recapitulated in our mouse model. Furthermore, we show that perturbation of interneuron subpopulations is an important mechanism underling the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. Given the frequency of ARX mutations in patients with infantile spasms and related disorders, our data unveil a new model for further understanding the pathogenesis of these disorders.
Marsh
Eric
E
Abramson Research Center, Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA. marshe@email.chop.edu
Fulp
Carl
C
Gomez
Ernest
E
Nasrallah
Ilya
I
Minarcik
Jeremy
J
Sudi
Jyotsna
J
Christian
Susan L
SL
Mancini
Grazia
G
Labosky
Patricia
P
Dobyns
William
W
Brooks-Kayal
Amy
A
Golden
Jeffrey A
JA
D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005838:Genotype; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D007395:Interneurons / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011944:Receptors, Androgen / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D049951:X Chromosome Inactivation
C469265:ARX protein, mouse; D018398:Homeodomain Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors