Otud7a Knockout Mice Recapitulate Many Neurological Features of 15q13.3 Microdeletion Syndrome

Am J Hum Genet. 2018 Feb 1;102(2):296-308. doi: 10.1016/j.ajhg.2018.01.005.


15q13.3 microdeletion syndrome is characterized by a wide spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, epilepsy, language impairment, abnormal behaviors, neuropsychiatric disorders, and hypotonia. This syndrome is caused by a deletion on chromosome 15q, which typically encompasses six genes. Here, through studies on OTU deubiquitinase 7A (Otud7a) knockout mice, we identify OTUD7A as a critical gene responsible for many of the cardinal phenotypes associated with 15q13.3 microdeletion syndrome. Otud7a-null mice show reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalizations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle. We show that OTUD7A localizes to dendritic spines and that Otud7a-null mice have decreased dendritic spine density compared to their wild-type littermates. Furthermore, frequency of miniature excitatory postsynaptic currents (mEPSCs) is reduced in the frontal cortex of Otud7a-null mice, suggesting a role of Otud7a in regulation of dendritic spine density and glutamatergic synaptic transmission. Taken together, our results suggest decreased OTUD7A dosage as a major contributor to the neurodevelopmental phenotypes associated with 15q13.3 microdeletion syndrome, through the misregulation of dendritic spine density and activity.

Keywords: 15q13.3 microdeletion syndrome; OTUD7A; dendritic spines; mouse behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Base Sequence
  • Behavior, Animal
  • Chromosome Deletion
  • Chromosome Disorders / enzymology*
  • Chromosome Disorders / genetics*
  • Chromosomes, Human, Pair 15 / enzymology
  • Chromosomes, Human, Pair 15 / genetics
  • Dendritic Spines / metabolism
  • Deubiquitinating Enzymes / genetics*
  • Disease Models, Animal
  • Electroencephalography
  • Endopeptidases / deficiency
  • Endopeptidases / genetics*
  • Epilepsy / enzymology
  • Epilepsy / genetics
  • Epilepsy / physiopathology
  • Female
  • Homozygote
  • Intellectual Disability / enzymology*
  • Intellectual Disability / genetics*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Seizures / enzymology*
  • Seizures / genetics*
  • Synapses / metabolism


  • Endopeptidases
  • Deubiquitinating Enzymes
  • Otud7a protein, mouse

Supplementary concepts

  • Chromosome 15q13.3 Microdeletion Syndrome