A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

ABSTRACT: The 22q11.2 deletion syndrome (22q11.2DS) is the most common copy number variant (CNV)-associated syndrome, leading to congenital and neuropsychiatric anomalies. Patient-derived, induced pluripotent stem cell (iPS) models have provided important insight into the mechanisms of phenotypic features of this condition. However, patient-derived iPSC models may harbor underlying genetic heterogeneity that can confound analysis of pathogenic CNV effects. Furthermore, the ~1.5 Mb “A-B” deletion at this locus is inherited at higher frequency than the more common ~2.7 Mb “A-D” deletion, but remains under-studied due to lack of relevant models. To address these issues, here we leveraged a CRISPR-based strategy in Cas9-expressing iPS cells to engineer novel isogenic models of the 22q11.2 “A-B” deletion. After in vitro differentiation to excitatory neurons, integrated transcriptomic and cell surface proteomics identified deletion-associated alterations in surface adhesion markers. Furthermore, implantation of iPS-derived neuronal progenitor cells into the cortex of neonatal mice found decreased proliferation and accelerated neuronal maturation within a relevant microenvironment. Taken together, our results suggest potential pathogenic mechanisms of the 22q11.2 “A-B” deletion in driving neuronal and neurodevelopmental phenotypes. We further propose that the isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell, Cell Culture, Excitatory Neuron

DISEASE(S): Genetic Disease

SUBMITTER: Yu-Hsiu Lin  

LAB HEAD: Arun P. Wiita

PROVIDER: PXD032075 | Pride | 2023-05-11

REPOSITORIES: Pride