Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes

Abstract

Background: Genetic defects affecting subunits of protein complexes are presumed to generate identical diseases in mammals. Results: Two mouse mutants in genes belonging to the BLOC-1 complex have divergent brain and pigmentation phenotypes. Conclusion: Genetic defects affecting subunits of a complex manifest by partially overlapping clinical features. Significance: Disease resulting from mutations in protein complexes may generate a wide range of clinically presentations.

Dysbindin-1C Is Required for the Survival of Hilar Mossy Cells and the Maturation of Adult Newborn Neurons in Dentate Gyrus

“…However, dysbindin-1C was not altered in the brain extracts of these mutants (Fig. 1G), consistent with the finding that dysbindin-1A, but not -1C, was reduced in mu mice (7,39). This result further supports the notion that dysbindin-1C does not reside in the BLOC-1 complex.…”

“…Currently, there is no support for MUTED as a susceptibility gene for schizophrenia (47). A recent study has shown the distinct effects on the expression of postsynaptic receptors in the HF between sdy and mu mice (39), supporting the notion that lack of different BLOC-1 subunits may lead to variable phenotypes, due to their different interac- (1). Hilar mossy cell and GABA interneuron, immature, and mature newborn granule neuron are marked with calretinin and GAD67, DCX, and NeuN, respectively.…”

Biogenesis of Lysosome-related Organelles Complex-1 Subunit 1 (BLOS1) Interacts with Sorting Nexin 2 and the Endosomal Sorting Complex Required for Transport-I (ESCRT-I) Component TSG101 to Mediate the Sorting of Epidermal Growth Factor Receptor into Endosomal Compartments

“…It must be emphasized that the above-mentioned functions may be attributable to specific BLOC-1 subunits rather than the whole BLOC-1 complex. Phenotypic differences exist in pigmentation and hippocampal postsynaptic receptor expression and adult neurogenesis between dysbindin-1-deficient mice and muted deficient mice (19,20).…”

Impaired Autophagy in Hilar Mossy Cells of the Dentate Gyrus and Its Implication in Schizophrenia

“…Yuan et al / Journal of Genetics and Genomics 42 (2015) 1e8 Larimore et al, 2014;Wang et al, 2014). This suggests that the dysbindin isoforms and the interactomes of different BLOC-1 subunits (Li et al, 2007) may underlie this phenotypic difference.…”