Alternative titles; symbols
HGNC Approved Gene Symbol: DTNBP1
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38) : 6:15,522,807-15,663,058 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.3 | Hermansky-Pudlak syndrome 7 | 614076 | Autosomal recessive | 3 |
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).
Using mouse beta-dystrobrevin (DTNB; 602415) in a yeast 2-hybrid screen, Benson et al. (2001) cloned dysbindin from adult mouse brain and myotube cDNA libraries. The deduced 352-amino acid protein has a calculated molecular mass of about 40 kD and contains a coiled-coil domain. Northern blot analysis revealed variable expression of dysbindin in all mouse tissues examined. Immunostaining of mouse muscle showed colocalization with alpha-dystrobrevin (DTNA; 601239) at the sarcolemma of most muscle fibers and in large blood vessels. Immunostaining of mouse brain sections revealed dysbindin confined to neurons, with no significant labeling of glial cells. Dysbindin localized primarily in axon bundles and especially in certain axon terminals, notably mossy fiber synaptic terminals in the cerebellum and hippocampus.
By database analysis, Tang et al. (2009) identified 3 DTNBP1 splice variants, which they termed dysbindin-1A, -1B, and -1C. The full-length dysbindin-1A contains 351 amino acids. The dysbindin-1B isoform is 303 amino acids and lacks the C-terminal PEST domain, whereas dysbindin-1C is 270 amino acids and lacks the N-terminal region in front of the coiled-coil domain. Tissue fractionation studies on the dorsolateral prefrontal cortex, anterior cingulate gyrus, superior temporal gyrus, and hippocampus showed that dysbindin-1C was concentrated only in synapses with a small amount associated with synaptic vesicles and a large amount in postsynaptic densities.
Using yeast 2-hybrid screens and coimmunoprecipitation experiments, Benson et al. (2001) determined that the C terminus of mouse dysbindin interacts directly with both Dtna and Dtnb. Immunolocalization in transfected COS-7 cells indicated diffuse cytoplasmic and nuclear staining that did not colocalize with Dtnb, which was concentrated in perinuclear punctae. When cotransfected, dysbindin expression caused relocalization of Dtnb into a diffuse cytoplasmic pattern. Benson et al. (2001) found that dysbindin was significantly upregulated in dystrophin (300377)-deficient (mdx) mouse skeletal muscle. Levels of dysbindin in total muscle extracts from mdx mice showed an approximately 5-fold increase when compared with normal muscle, and immunostaining revealed upregulation at the sarcolemma of all fibers coincident with a reduction of intrafiber labeling.
Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC; see 602415) in both muscle and nonmuscle cells (Benson et al., 2001). Li et al. (2003) showed that dysbindin is a component of the biogenesis of lysosome-related organelles complex-1 (BLOC1), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin (PLDN; 604310), muted (MU; 607289), and cappuccino (CNO; 605695). These proteins are associated with Hermansky-Pudlak syndrome (HPS; 203300) in mice; Li et al. (2003) found mutation in the human DTNBP1 gene in an individual with HPS. The findings of Li et al. (2003) showed that BLOC1 is important in producing the HPS phenotype in humans, indicated that dysbindin has a role in the biogenesis of lysosome-related organelles, and identified unexpected interactions between components of DPC and BLOC1.
By in situ hybridization, Talbot et al. (2004) found dysbindin-1 expression in all principal neuronal populations of the hippocampus, including pyramidal cells, granule cells, and polymorph cells. The dysbindin-1 protein was located in presynaptic axon terminals of glutamatergic pathways. In schizophrenia (see 181500) cases, there was a significant reduction of dysbindin-1 in the terminal fields of intrinsic glutamatergic connections of the hippocampus compared to controls, although reductions were not seen in other brain areas, such as the anterior cingulate cortex. The reduction of presynaptic dysbindin-1 was independent of beta-dystrobrevin and the dystrophin glycoprotein complex. Talbot et al. (2004) suggested that the changes may contribute to the cognitive defects in schizophrenia.
In rat cortical neurons, Numakawa et al. (2004) showed that overexpression of dysbindin induced expression of 2 presynaptic proteins, SNAP25 (600322) and synapsin I (SYN1; 313440), and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in reduction of presynaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in presynaptic machinery. Overexpression of dysbindin increased phosphorylation of Akt (164730) and protected cortical neurons against neuronal death due to serum deprivation; these effects were blocked by a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin may promote neuronal viability through PI3-kinase-Akt signaling.
To better understand how neural function is stabilized during development and throughout life, Dickman and Davis (2009) used an electrophysiology-based forward genetic screen and assessed the function of more than 250 neuronally expressed genes for a role in the homeostatic modulation of synaptic transmission in Drosophila. This screen ruled out the involvement of numerous synaptic proteins and identified a critical function for dysbindin, a gene linked to schizophrenia in humans (see 600511). Dickman and Davis (2009) found that dysbindin is required presynaptically for the retrograde, homeostatic modulation of neurotransmission, and functions in a dose-dependent manner downstream or independently of calcium influx. Thus, Dickman and Davis (2009) concluded that dysbindin is essential for adaptive neural plasticity and may link altered homeostatic signaling with a complex neurologic disease.
Locke et al. (2009) showed that TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. TRIM32 bound and ubiquitinated dysbindin, augmenting its degradation. Knockdown of TRIM32 in myoblasts resulted in elevated levels of dysbindin.
Using brain samples from 28 Caucasian schizophrenia patients and 28 age- and sex-matched controls, Tang et al. (2009) reported that Western blotting of whole-tissue lysates of dorsolateral prefrontal cortex (DLPFC) revealed significant reductions in dysbindin-1C (but not in dysbindin-1A or -1B) in schizophrenia (p = 0.022). These reductions occurred without any significant change in levels of the encoding transcript in the same tissue samples and in the absence of the only DTNBP1 risk haplotype for schizophrenia reported in the United States (see Funke et al. (2004) and 600511). No significant correlations were found between case-control differences in any dysbindin-1 isoform and the case-control differences in its encoding mRNA. The mean 60% decrease in dysbindin-1C observed in 71% of the case-control pairs appeared to reflect abnormalities in mRNA translation and/or processes promoting dysbindin-1C degradation. Given the predominantly postsynaptic localization of dysbindin-1C and known postsynaptic effects of dysbindin-1 reductions in the rodent equivalent of the DLPFC, Tang et al. (2009) suggested that decreased dysbindin-1C in the DLPFC may contribute to the cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction in fast-spiking interneurons.
Gross (2015) mapped the DTNBP1 gene to chromosome 6p22.3 based on an alignment of the DTNBP1 sequence (GenBank AF061734) with the genomic sequence (GRCh38).
Hermansky-Pudlak Syndrome 7
Li et al. (2003) screened for mutations in the 10 exons of the DTNBP1 gene in 22 unrelated non-Puerto Rican individuals with Hermansky-Pudlak syndrome (HPS) who did not have mutations in HPS1 (604982), HPS3 (606118), HPS4 (606682), HPS5 (607521), or HPS6 (607522). In a Portuguese woman with HPS7 (614076), they found homozygosity for a truncating mutation in the DTNBP1 gene (Q103X; 607145.0001).
In a 77-year-old Caucasian woman, born of consanguineous parents, with HPS7, Lowe et al. (2013) identified a homozygous truncating mutation in the DTNBP1 gene (W59X; 607145.0002). The mutation was found by autozygosity mapping with microsatellite markers followed by direct sequencing of the candidate DTNBP1 gene.
In a 6-year-old Paraguayan boy with HPS7, Bryan et al. (2017) identified homozygosity for the previously identified Q103X mutation in the DTNBP1 gene. Patient fibroblasts showed normal DTNBP1 mRNA expression but negligible dysbindin protein expression.
Association of DTNBP1 with Schizophrenia Risk
For a discussion of the relationship between variation in the DTNBP1 gene and risk of schizophrenia, see SCZD3 (600511).
Hermansky-Pudlak syndrome (203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding, and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles such as melanosomes and platelet-dense granules. In mice, at least 16 loci are associated with HPS, including 'sandy' (sdy) (Swank et al., 1991). Li et al. (2003) showed that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1. They confirmed that mutation of dysbindin causes the sdy phenotype and that dysbindin is important for normal platelet-dense granule and melanosome biogenesis.
Tang et al. (2009) found that hippocampal neurons derived from Dtnbp1-null mice had about a 50% increase in surface expression of Nr2a (138253), a subunit of the tetrameric NMDA receptor, compared to control, whereas surface expression of Nr2b (138252) was unaffected. Western blot analysis showed no difference in levels of these proteins in the adult hippocampus of mutant mice compared to wildtype. Expression of dysbindin reduced Nr2a surface expression in both wildtype and Dtnbp1-null neurons. Electrophysiologic recordings of Dtnbp1-null hippocampal slices showed an increase in NMDA receptor excitatory postsynaptic currents mediated by Nr2a as well as an increase in long-term potentiation, suggesting an alteration in synaptic plasticity in the hippocampus. Basal synaptic transmission and long-term depression were normal. The findings suggested that murine dysbindin controls hippocampal long-term potentiation by selective and direct regulation of the surface expression of Nr2a. Tang et al. (2009) noted that Nr2a undergoes postendocytic sorting through the lysosomal pathway. They suggested that knockout of dysbindin may divert endocytosed membrane proteins back to the cell surface rather than to the lysosome.
In a 48-year-old Portuguese woman with Hermansky-Pudlak syndrome (HPS7; 614076), Li et al. (2003) found homozygosity for a 307C-T transition in the DTNBP1 gene resulting in the amino acid substitution gln103 to ter (Q103X) in homozygous state. Bleeding time was 13 minutes, and platelet aggregation indicated a storage-pool deficiency. The woman had mild shortness of breath on exertion and reduced lung compliance but otherwise normal pulmonary function and high resolution computed tomography (CT) chest scans, and had no muscle weakness or ataxia. Her parents were first cousins.
In a 6-year-old Paraguayan boy with HPS in whom no mutations in other genes associated with HPS were found, Bryan et al. (2017) identified homozygosity for the Q103X mutation in the DTNBP1 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. DNA of the parents was not tested. Patient fibroblasts showed normal DTNBP1 mRNA levels but markedly reduced dysbindin protein expression. The authors noted that the Q103X mutation had a low frequency in the ExAC database, being reported in only 2 of 120,818 alleles from multiple populations.
In a 77-year-old Caucasian woman, born of consanguineous parents, with Hermansky-Pudlak syndrome-7 (HPS7; 614076), Lowe et al. (2013) identified a homozygous c.177G-A transition in exon 4 of the DTNBP1 gene, resulting in a trp59-to-ter (W59X) substitution. The mutation was found by autozygosity mapping with microsatellite markers followed by direct sequencing of the candidate DTNBP1 gene. The patient had a lifelong bleeding tendency, pale skin and hair, and lifelong reduced visual acuity and nystagmus. She had no evidence of pulmonary disease but did have granulomatous colitis diagnosed as Crohn disease. Platelet studies showed impaired aggregation responses and a lack of dense granule secretion.
Benson, M. A., Newey, S. E., Martin-Rendon, E., Hawkes, R., Blake, D. J. Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain. J. Biol. Chem. 276: 24232-24241, 2001. [PubMed: 11316798] [Full Text: https://doi.org/10.1074/jbc.M010418200]
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Funke, B., Finn, C. T., Plocik, A. M., Lake, S., DeRosse, P., Kane, J. M., Kucherlapati, R., Malhotra, A. K. Association of the DTNBP1 locus with schizophrenia in a U.S. population. Am. J. Hum. Genet. 75: 891-898, 2004. [PubMed: 15362017] [Full Text: https://doi.org/10.1086/425279]
Gross, M. B. Personal Communication. Baltimore, Md. 2/17/2015.
Li, W., Zhang, Q., Oiso, N., Novak, E. K., Gautam, R., O'Brien, E. P., Tinsley, C. L., Blake, D. J., Spritz, R. A., Copeland, N. G., Jenkins, N. A., Amato, D., Roe, B. A., Starcevic, M., Dell'Angelica, E. C., Elliott, R. W., Mishra, V., Kingsmore, S. F., Paylor, R. E., Swank, R. T. Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nature Genet. 35: 84-89, 2003. [PubMed: 12923531] [Full Text: https://doi.org/10.1038/ng1229]
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Swank, R. T., Sweet, H. O., Davisson, M. T., Reddington, M., Novak, E. K. Sandy: a new mouse model for platelet storage pool deficiency. Genet. Res. 58: 51-62, 1991. [PubMed: 1936982] [Full Text: https://doi.org/10.1017/s0016672300029608]
Talbot, K., Eidem, W. L., Tinsley, C. L., Benson, M. A., Thompson, E. W., Smith, R. J., Hahn, C.-G., Siegel, S. J., Trojanowski, J. Q., Gur, R. E., Blake, D. J., Arnold, S. E. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J. Clin. Invest. 113: 1353-1363, 2004. [PubMed: 15124027] [Full Text: https://doi.org/10.1172/JCI20425]
Tang, J., LeGros, R. P., Louneva, N., Yeh, L., Cohen, J. W., Hahn, C.-G., Blake, D. J., Arnold, S. E., Talbot, K. Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Hum. Molec. Genet. 18: 3851-3863, 2009. [PubMed: 19617633] [Full Text: https://doi.org/10.1093/hmg/ddp329]
Tang, T. T.-T., Yang, F., Chen, B.-S., Lu, Y., Ji, Y., Roche, K. W., Lu, B. Dysbindin regulates hippocampal LTP by controlling NMDA receptor surface expression. Proc. Nat. Acad. Sci. 106: 21395-21400, 2009. [PubMed: 19955431] [Full Text: https://doi.org/10.1073/pnas.0910499106]