Analysis of UBE3A- and NHE6-mutant cells to determine social communication gene networks

  • Awarded: 2018
  • Award Type: Explorer
  • Award #: 600432

Genetic research in autism has led to the discovery of a growing list of highly penetrant mutations that contribute to disease pathophysiology. This recent progress provides an important opportunity to define the molecular mechanisms in autism and related disorders, as well as to identify targets for new treatment strategies. However, the number of high-confidence loci is growing large, estimated in the hundreds; therefore, treatment strategies targeting these mechanisms individually may be quite daunting. As a result, a major new challenge for autism research is to establish convergent mechanisms that group apparently distinct genetic etiologies.

Eric Morrow and his research group plan to focus on two disease-associated proteins: the E3 ubiquitin ligase UBE3A/E6-AP and the Na+/H+ exchanger family member 6 (NHE6/SLC9A6). Genetic mutations affecting these proteins are associated with overlapping clinical syndromes, Angelman syndrome and Christianson syndrome respectively. Overlapping clinical phenotypes are also noted with Dup15q syndrome, which results from duplication of the genomic interval containing the UBE3A gene. Given the shared clinical spectra affecting social communication, UBE3A and NHE6 may function in a convergent cellular pathway with relevance to autism. Morrow proposes to investigate the overlapping function of UBE3A and NHE6 by comparing transcriptome profiles in induced pluripotent stem cell (iPSC)-derived neurons and primary mouse cortical neurons that harbor null mutations in UBE3A versus NHE6.

He and his team will also compare transcriptome profiles in cells that harbor gain-of-function mutations in UBE3A versus null mutations in NHE6. They will generate and interrogate data in isogenic cell lines using batch RNA sequencing (RNA-Seq), as well as in mouse fronto-cortical neurons from juvenile animals lacking expression of Ube3a or Nhe6 using single cell RNA-sequencing (scRNA-Seq). Morrow’s objective is to identify points of convergence in gene networks and cellular mechanisms perturbed in cells mutant for UBE3A or NHE6 that are related to autism or social communication. The discovery of a mechanistic interaction between UBE3A and NHE6 would have broad impact on the field of neurodevelopmental disorders, including autism.

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