Alternative titles; symbols
HGNC Approved Gene Symbol: DTNA
Cytogenetic location: 18q12.1 Genomic coordinates (GRCh38): 18:34,493,312-34,891,844 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.1 | Left ventricular noncompaction 1, with or without congenital heart defects | 604169 | Autosomal dominant | 3 |
By searching an EST database for novel dystrophin (300377)-related genes, followed by screening human adult brain and skeletal muscle cDNA libraries, Sadoulet-Puccio et al. (1996) cloned dystrobrevin. The largest ORF in the dystrobrevin gene shows 50% homology to the cysteine-rich and C-terminal domains of dystrophin, and 84% homology to a phosphoprotein found in the electric organ postsynaptic membrane in Torpedo californica. Five distinct mRNA transcripts were preferentially expressed in different tissues.
Newey et al. (2001) stated that 3 Dtna isoforms are expressed in mouse skeletal muscle. The longest isoform, Dtna1, contains an N-terminal EF-hand region, followed by zinc-binding ZZ domain, a muscle-expressed variable region, 2 coiled-coil regions, and a C-terminal domain with a tyrosine phosphorylation motif. Dtna1 also has 2 syntrophin (see SNTA1; 601017)-binding sites that overlap the variable region and a dystrophin-binding site that overlaps the first coiled-coil domain. Dtna2 lacks part of the C-terminal domain, including the tyrosine phosphorylation motif, and Dtna3 lacks the variable region and coiled-coil domains.
Sadoulet-Puccio et al. (1997) determined that the DTNA gene contains 23 exons and spans at least 180 kb. Three different C termini of dystrobrevin are generated by mutually exclusive mRNA splicing of 3 exons. Two alternatively spliced exons (exons 11A and 12) are used exclusively in striated muscle. A comparison of the genomic organization of dystrophin and dystrobrevin showed that the 2 genes have significant similarities in their genomic structure, implying an ancestral or evolutionary relationship.
Khurana et al. (1994) mapped an EST corresponding to the DTNA gene to chromosome 18q12.1-q12.2 by FISH.
Ambrose et al. (1997) mapped the mouse homolog of dystrobrevin to proximal mouse chromosome 18.
The dystrophin-associated protein complex (DPC), located at the sarcolemma, can be divided into 3 subcomplexes: the dystroglycan complex, the sarcoglycan complex, and the cytoplasmic complex. The last consists of 2 families of proteins, the syntrophins and dystrobrevin. Metzinger et al. (1997) found that anti-dystrobrevin antibodies stain the sarcolemma in normal skeletal muscle, indicating that dystrobrevin colocalizes with dystrophin and the dystrophin-associated protein complex. By contrast, dystrobrevin membrane staining was severely reduced in muscles of Duchenne muscular dystrophy patients and also dramatically reduced in patients with limb-girdle muscular dystrophy arising from the loss of 1 or all of the sarcoglycan components (e.g., LGMD2C; 253700). Normal dystrobrevin staining was observed in patients with other forms of limb-girdle muscular dystrophy where dystrophin and the rest of the dystrophin-associated protein complex are normally expressed (e.g., LGMD2A; 253600), as well as in other neuromuscular disorders. Their results showed that dystrobrevin deficiency is a generic feature of dystrophies linked to dystrophin and the dystrophin-associated proteins. This was the first indication that a cytoplasmic component of the dystrophin-associated protein complex may be involved in the pathogenesis of limb-girdle muscular dystrophy.
Yoshida et al. (2000) found that the N-terminal half of dystrobrevin participates in an association with the sarcoglycan-sarcospan complex. The authors hypothesized that the sarcoglycan-sarcospan complex is linked to the signaling protein neuronal nitric oxide synthase (163731) via alpha-syntrophin (601017) associated with dystrobrevin.
The mammalian dystrobrevin gene encodes several protein isoforms that are expressed in different tissues, including brain and muscle. Blake et al. (1998) reported a form of dystrobrevin, designated beta-dystrobrevin (602415) by them, a dystrophin-related protein that is abundantly expressed in brain and other tissues, but is not found in muscle. The dystrobrevin in muscle was designated alpha-dystrobrevin.
Using yeast 2-hybrid analysis and coimmunoprecipitation analysis of transfected COS-7 cells, Newey et al. (2001) showed that the mouse intermediate filament protein syncoilin (SYNC1; 611750) interacted with mouse Dtna1 and Dtna2. Dtna and syncoilin colocalized at the neuromuscular junction of skeletal muscle. Newey et al. (2001) concluded that DTNA provides a link between dystrophin protein complex and the intermediate filament network at the neuromuscular junction.
Left Ventricular Noncompaction 1
In a 4-generation Japanese family with left ventricular noncompaction-1 (LVNC1; 604169), Ichida et al. (2001) analyzed the DTNA gene and identified heterozygosity for a missense mutation (P121L; 601239.0001) in affected members that was not found in unaffected family members or in 300 age- and sex-matched controls.
In a 39-year-old man with a diagnosis of LVNC, in whom mutations in 8 candidate genes were excluded, Cao et al. (2017) identified a heterozygous missense mutation in the DTNA gene (N49S; 601239.0002) by Sanger sequencing. The mutation was not found in the NHLBI ESP or 1000 Genomes Project databases or in 400 ethnically matched controls. A cardiac-specific transgenic mouse model that overexpressed Dtna with the N49S mutation was found to have a progressive cardiomyopathy characterized by dilated and thinner LV, cardiac systolic dysfunction, and age-related LV hypertrabeculation.
Associations Pending Confirmation
For discussion of a possible association between variation in the DTNA gene and susceptibility to Meniere disease, see 156000.
In 6 affected members of a 4-generation Japanese family with left ventricular noncompaction-1 (LVNC1; 604169), Ichida et al. (2001) identified heterozygosity for a 362C-T transition in exon 3 of the DTNA gene, resulting in a pro121-to-leu (P121L) substitution. Protein sequence analysis predicted that the P121L substitution would result in the reduction of an alpha-helix by 2 amino acids and the removal of a loop in this portion of the protein, which encodes the calcium-binding EF-hand domain, possibly resulting in a significant secondary structural change. Five of the 6 affected family members had other congenital heart defects, primarily one or more ventricular septal defects, in addition to LVNC. The mutation was not found in unaffected family members or in 300 age- and sex-matched controls (200 of which were Japanese and 100 Caucasian).
In a 39-year-old man with a diagnosis of left ventricular noncompaction (LVNC1; 604169), in whom mutations in 8 candidate genes were excluded, Cao et al. (2017) identified a heterozygous c.146A-G transition in the DTNA gene, resulting in an asn49-to-ser (N49S) substitution at a highly conserved residue in the WW domain. The mutation was not found in the NHLBI ESP or 1000 Genomes Project databases or in 400 ethnically matched controls. A cardiac-specific transgenic mouse model that overexpressed Dtna with the N49S mutation was found to have a progressive cardiomyopathy characterized by dilated and thinner LV, cardiac systolic dysfunction, and age-related LV hypertrabeculation.
Ambrose, H. J., Blake, D. J., Nawrotzki, R. A., Davies, K. E. Genomic organization of the mouse dystrobrevin gene: comparative analysis with the dystrophin gene. Genomics 39: 359-369, 1997. [PubMed: 9119373] [Full Text: https://doi.org/10.1006/geno.1996.4515]
Blake, D. J., Nawrotzki, R., Loh, N. Y., Gorecki, D. C., Davies, K. E. Beta-dystrobrevin, a member of the dystrophin-related protein family. Proc. Nat. Acad. Sci. 95: 241-246, 1998. [PubMed: 9419360] [Full Text: https://doi.org/10.1073/pnas.95.1.241]
Cao, Q., Shen, Y., Liu, X., Yu, X., Yuan, P., Wan, R., Liu, X., Peng, X., He, W., Pu, J., Hong, K. Phenotype and functional analyses in a transgenic mouse model of left ventricular noncompaction caused by a DTNA mutation. Int. Heart J. 58: 939-947, 2017. [PubMed: 29118297] [Full Text: https://doi.org/10.1536/ihj.16-019]
Ichida, F., Tsubata, S., Bowles, K. R., Haneda, N., Uese, K., Miyawaki, T., Dreyer, W. J., Messina, J., Li, H., Bowles, N. E., Towbin, J. A. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 103: 1256-1263, 2001. [PubMed: 11238270] [Full Text: https://doi.org/10.1161/01.cir.103.9.1256]
Khurana, T. S., Engle, E. C., Bennett, R. R., Silverman, G. A., Selig, S., Bruns, G. A. P., Kunkel, L. M. (CA) repeat polymorphism in the chromosome 18 encoded dystrophin-like protein. Hum. Molec. Genet. 3: 841 only, 1994. [PubMed: 8081380] [Full Text: https://doi.org/10.1093/hmg/3.5.841-a]
Metzinger, L., Blake, D. J., Squier, M. V., Anderson, L. V. B., Deconinck, A. E., Nawrotzki, R., Hilton-Jones, D., Davies, K. E. Dystrobrevin deficiency at the sarcolemma of patients with muscular dystrophy. Hum. Molec. Genet. 6: 1185-1191, 1997. [PubMed: 9215691] [Full Text: https://doi.org/10.1093/hmg/6.7.1185]
Newey, S. E., Howman, E. V., Ponting, C. P., Benson, M. A., Nawrotzki, R., Loh, N. Y., Davies, K. E., Blake, D. J. Syncoilin, a novel member of the intermediate filament superfamily that interacts with alpha-dystrobrevin in skeletal muscle. J. Biol. Chem. 276: 6645-6655, 2001. [PubMed: 11053421] [Full Text: https://doi.org/10.1074/jbc.M008305200]
Sadoulet-Puccio, H. M., Feener, C. A., Schaid, D. J., Thibodeau, S. N., Michels, V. V., Kunkel, L. M. The genomic organization of human dystrobrevin. Neurogenetics 1: 37-42, 1997. [PubMed: 10735273] [Full Text: https://doi.org/10.1007/s100480050006]
Sadoulet-Puccio, H. M., Khurana, T. S., Cohen, J. B., Kunkel, L. M. Cloning and characterization of the human homologue of a dystrophin related phosphoprotein found at the Torpedo electric organ post-synaptic membrane. Hum. Molec. Genet. 5: 489-496, 1996. [PubMed: 8845841] [Full Text: https://doi.org/10.1093/hmg/5.4.489]
Yoshida, M., Hama, H., Ishikawa-Sakurai, M., Imamura, M., Mizuno, Y., Araishi, K., Wakabayashi-Takai, E., Noguchi, S., Sasaoka, T., Ozawa, E. Biochemical evidence for association of dystrobrevin with the sarcoglycan-sarcospan complex as a basis for understanding sarcoglycanopathy. Hum. Molec. Genet. 9: 1033-1040, 2000. [PubMed: 10767327] [Full Text: https://doi.org/10.1093/hmg/9.7.1033]