Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes.
J Biol Chem
; 289(20): 14291-300, 2014 May 16.
Article
de En
| MEDLINE
| ID: mdl-24713699
ABSTRACT
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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Phénotype
/
Protéines de transport
/
Sous-unités de protéines
/
Protéines du transport vésiculaire
/
Protéines mutantes
/
Mutation
Type d'étude:
Etiology_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
J Biol Chem
Année:
2014
Type de document:
Article