The human gene DTNBP1 has been proposed as a candidate susceptibility locus for schizophrenia (see MIM:600511). This gene encodes a component of the multi-subunit protein complex BLOC-1 (biogenesis of lysosomal organelles complex 1). There is a high-scoring ortholog in Drosophila, Dysb , for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. DTNBP1 has also been associated with Hermansky-Pudlak syndrome 7 (MIM:614076, FBhh0000251).
A UAS construct of the human Hsap\DTNBP1 gene has been introduced into flies. Partial heterologous rescue (functional complementation) has been observed for phenotypes of a hypomorphic mutation of Dmel\Dysb.
Loss-of-function mutations of Dysb result in defects in behavior, learning, memory, and neurophysiology. Phenotypes of homozygous loss-of-function alleles of Dysb were compared to those of Dmel\Blos1, which encodes another subunit the BLOC-1 complex. Similar phenotypes, including impaired neurotransmitter release, synapse morphology, and homeostatic plasticity at the larval neuromuscular junction, and impaired olfactory habituation were observed for both; these phenotypes are also observed for compound heterozygotes involving LOF alleles of the two genes (see FBhh0000527). Physical interactions and additional genetic interactions of Dmel\Dysb have been described; see below and in the Dysb gene report.
Based in part on work in flies, the human genes DTNBP1 and BLOC1S1, subunits of the BLOC-1 complex orthologous to Dmel\Dysb and Dmel\Blos1, are both postulated to have an association with Hermansky-Pudlak syndrome and to contribute to susceptibility to schizophrenia.
[updated Nov. 2020 by FlyBase; FBrf0222196]
See also 'Schizophrenia: Symptoms, causes, and treatments' (http://www.medicalnewstoday.com/articles/36942.php).
Schizophrenia is a psychosis, a disorder of thought and sense of self. Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Schizophrenia often develops in young adults who were previously normal, and is characterized by a constellation of symptoms including hallucinations and delusions (psychotic symptoms) and symptoms such as severely inappropriate emotional responses, disordered thinking and concentration, erratic behavior, as well as social and occupational deterioration (Andreasen, 1995; pubmed:7637483). [from MIM:181500; 2017.04.18]
Using data from a regularly updated online database of all published genetic association studies for schizophrenia (SzGene), Allen et al. (2008; pubmed:18583979) carried out random-effects metaanalyses for all polymorphisms having genotype data available in at least 4 independent case-control samples. Associations with variants of DTNBP1 were characterized as showing 'strong' epidemiologic credibility. [from MIM:181500; 2017.07.17]
The protein encoded by the DTNBP1 gene is a component of the multisubunit protein complex BLOC-1 (biogenesis of lysosomal organelles complex 1). Among other functions, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals; it is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system. [from Gene Cards, DTNBP1; 2017.04.18]
The DYNBP1 gene encodes dysbindin, a key component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), which regulates the trafficking of proteins in the lysosomal pathway (summary by Tang et al., 2009; pubmed:19955431). [from MIM:607145; 2017.04.18]
Many to one: 3 human to 1 Drosophila; the additional human genes are DBNDD2 and DBNDD1.
High-scoring ortholog of human DTNBP1; low-scoring ortholog of two additional human genes, DBNDD2 and DBNDD1 (3 human to 1 Drosophila). Dmel\Dysb shares 25% identity and 46% similarity with DTNBP1.
