HGNC Approved Gene Symbol: BRDT
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38): 1:91,949,371-92,014,428 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p22.1 | ?Spermatogenic failure 21 | 617644 | Autosomal recessive | 3 |
In a database search for members of the RING3 (601540) family, Jones et al. (1997) identified an EST derived from a testis-specific library. A study of cDNA clones indicated that the gene encodes a protein of 947 amino acids with extensive homology to RING3 and to the Drosophila developmental gene fsh. Similar to these proteins, it possesses 2 bromodomain motifs and a PEST sequence (a cluster of proline, glutamic acid, serine, and threonine residues), characteristic of proteins that undergo rapid intracellular degradation. The bromodomain is a motif of 59 to 63 amino acids thought to be involved in protein-protein interaction. It is found in proteins that regulate transcription. Northern analysis of 16 normal tissues and 8 cancer cell lines showed transcripts of 3.5 and 4.0 kb expressed specifically in testis.
Gaucher et al. (2012) analyzed Brdt expression during spermatogenic differentiation in prepubertal and adult mouse testis. The first detectable accumulation of Brdt mRNA corresponded to the period in which type B spermatogonia give rise to early meiotic cells (preleptotene, leptotene, and zygotene) at 10 to 12 days postpartum (dpp), with clearly detectable protein at 12 dpp. Staining of seminiferous tubules of adult mouse testes confirmed the absence of Brdt expression in spermatogonia as well as its expression in spermatogenic cells at later stages. The authors concluded that Brdt first acts during meiotic prophase of spermatogenic cells.
By PCR analysis of a panel of monochromosomal human/rodent hybrid cell lines and a Genebridge 4 panel of radiation hybrids, Jones et al. (1997) localized the BRDT gene to 1p.
Gaucher et al. (2012) demonstrated that Brdt in mouse testis is a master regulator of both meiotic division and postmeiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program. In meiotic and postmeiotic cells, Brdt initiates genuine histone acetylation-guided programming of the genome by activating essential genes and repressing a 'progenitor cells' gene expression program. At postmeiotic stages, global chromatin hyperacetylation gives the signal for Brdt's first bromodomain to direct the genomewide replacement of histones by transition proteins. Gaucher et al. (2012) concluded that Brdt is a unique and essential regulator of male germ cell differentiation which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program and later controls the tight packaging of the male genome.
In a Chinese man with spermatogenic failure (SPGF21; 617644) due to acephalic spermatozoa, Li et al. (2017) identified homozygosity for a missense mutation in the BRDT gene (G928D; 602144.0001).
Gaucher et al. (2012) observed total absence of postmeiotic cells in the testes of adult Brdt -/- mice: there was no expression of the acrosomal protein Sp56 (604188) in the seminiferous tubules and no round spermatids could be detected in DNA-stained tubule sections. Detailed analysis of spermatocytes in seminiferous tubule sections showed that earlier meiotic events occur normally.
In a Chinese man with spermatogenic failure (SPGF21; 617644) due to acephalic spermatozoa, Li et al. (2017) identified homozygosity for a c.2783G-A transition (c.2783G-A, NM_207189) in exon 19 of the BRDT gene, resulting in a gly928-to-asp (G928D) substitution at a highly conserved residue within the P-TEFb binding domain in the C terminus. The mutation was present in heterozygosity in his first-cousin parents and his fertile brother. The variant was found in the ExAC database in the East Asian population at a frequency of 0.0001. Transcriptome analysis revealed 899 genes that were significantly differently expressed between wildtype and mutant cells, and Gene Ontology analysis showed that the upregulated genes were enriched in intracellular transport, RNA splicing, cell cycle, and DNA metabolic processes. Only 1 biologic process, translational elongation, was enriched in genes downregulated in the mutant cells. Li et al. (2017) categorized G928D as a gain-of-function mutation.
Gaucher, J., Boussouar, F., Montellier, E., Curtet, S., Buchou, T., Bertrand, S., Hery, P., Jounier, S., Depaux, A., Vitte, A.-L., Guardiola, P., Pernet, K., Debernardi, A., Lopez, F., Holota, H., Imbert, J., Wolgemuth, D. J., Gerard, M., Rousseaux, S., Khochbin, S. Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J. 31: 3809-3820, 2012. [PubMed: 22922464] [Full Text: https://doi.org/10.1038/emboj.2012.233]
Jones, M. H., Numata, M., Shimane, M. Identification and characterization of BRDT: a testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. Genomics 45: 529-534, 1997. [PubMed: 9367677] [Full Text: https://doi.org/10.1006/geno.1997.5000]
Li, L., Sha, Y., Wang, X., Li, P., Wang, J., Kee, K., Wang, B. Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa. Oncotarget 8: 19914-19922, 2017. [PubMed: 28199965] [Full Text: https://doi.org/10.18632/oncotarget.15251]