Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes.
Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5(mu/mu)) and dysbindin (Bloc1s8(sdy/sdy)). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5(mu/mu) and Bloc1s8(sdy/sdy) mice. Unlike Bloc1s8(sdy/sdy), elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders.
From the Department of Biology, Agnes Scott College, Decatur, Georgia 30030.
Jennifer
J
Larimore
the Department of Cell Biology and.
Stephanie A
SA
Zlatic
the Department of Cell Biology and.
Avanti
A
Gokhale
the Department of Cell Biology and.
Karine
K
Tornieri
From the Department of Biology, Agnes Scott College, Decatur, Georgia 30030.
Kaela S
KS
Singleton
the Department of Cell Biology and.
Ariana P
AP
Mullin
the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and.
Junxia
J
Tang
the Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California 90048.
Konrad
K
Talbot
the Department of Cell Biology and the Center for Social Translational Neuroscience Emory University, Atlanta, Georgia 30322, vfaunde@emory.edu.
Victor
V
Faundez
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D018377:Neurotransmitter Agents / Q000378:metabolism; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002352:Carrier Proteins; C432416:DTNBP1 protein, human; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D050505:Mutant Proteins; D018377:Neurotransmitter Agents; D021122:Protein Subunits; D033921:Vesicular Transport Proteins; C000606739:muted protein, mouse; D005680:gamma-Aminobutyric Acid
Adaptor Proteins; Mouse Genetics; Protein Complexes; Schizophrenia; Synapses