DDX25 (DEAD (Asp-Glu-Ala-Asp) box helicase 25)

2012-02-01   Chon-Hwa Tsai-Morris , Maria L Dufau 

Section on Molecular Endocrinology, Program in Developmental Endocrinology, Genetics, NICHD, National Institutes of Health, Bethesda, MD 20892-4510, USA

Identity

HGNC
LOCATION
11q24.2
LOCUSID
ALIAS
GRTH
FUSION GENES

DNA/RNA

Atlas Image
Genomic organization of the Human GRTH gene. Exons presented by boxes. The positions of the translation initiation ATG and termination TGA codon are indicated. Conserved domains of DEAD-box family of the RNA helicase are presented above its respective exon.

Description

Human GRTH gene contains 12 exons and all but one of its conserved helicase motifs are contained within single exon (Tsai-Morris et al., 2004). Motif ARG-D resides in exon 10/11.

Transcription

The GRTH gene belongs to the TATA-less/non-initiator class (Tsai-Morris et al., 2004). A single transcript of 1,6 Kb is expressed in the testis (Tang et al., 1999). Gonadotropin-induced androgen increases cause autocrine stimulation of GRTH gene transcription in Leydig cells through a non-classical half-site element residing at -827/-822 5 from the initiation codon (Tang et al., 1999; Tsai-Morris et al., 2010; Villar et al., 2012). The induction of the GRTH gene expression in germ cells (meiotic spermatocytes, round and elongated spermatids) presumbably results from paracrine actions of androgen through cognate receptors in Sertoli cells (adjacent to germinal cells).

Pseudogene

One related pseudo DDX25 (LOC100421309) was found in chromosome 5.

Proteins

Description

GRTH contains three ATG in frame codons with the potential for generation of multiple protein species (61/56, 48/43 and 33 kDa) (Sheng et al., 2003). The 61/56 kDa proteins are the major species observed in the human testis (Tang et al., 1999; Tsai-Morris et al., 2007). GRTH 56- and 61-kDa species are present in nucleus and cytoplasm (Sheng et al., 2006), respectively. Based on the mouse model, the 56 kDa nuclear species interacts with CRM1 and participates in mRNA transport in the human testis and the phosphorylated 61 kDa species associates with mRNAs at polysomal sites and also within the Chromatoid Body of round spermatids.

Expression

GRTH (484 aa) is highly expressed in the testis: somatic (Leydig cells) and germinal (meiotic spermatocytes, round spermatids and elongated spermatids) cells (Sheng et al., 2003; Tsai-Morris, et al., 2004). GRTH is genetically close to DBP5/DDX19b (63% overall aa homology) involved in mRNA export (Schmitt et al., 1999).

Localisation

GRTH is localized in the nucleus and at cytoplasmic sites in polyribosomes and the Chromatoid Body (CB) of round spermatids (Tsai-Morris et al., 2004; Sheng et al., 2006; Sato et al., 2010; Tsai-Morris et al., 2012).

Function

GRTH is a multifunctional protein essential for completion of spermatogenesis as a post-transcriptional regulator of relevant genes during germ cells development (Tsai-Morris et al., 2004; Sheng et al., 2006; Dufau and Tsai-Morris, 2007; Tsai-Morris et al., 2010). It contains ATPase activity (ATP/Mg dependent), and is a bi-directional RNA helicase. As a translational regulator it participates in the in vitro and in vivo translation of RNA templates. GRTH is a shuttling protein that exports germ cell specific RNA as mRNP particles from nucleus to cytoplasm via the CRM1-dependent pathway. A specific set of testicular gene transcripts, including those of chromatin-remodeling proteins (Tp1 and Tp2, Prm1 and PRM2), cytoskeletal structural proteins (Fsc1/Odf1) and tACE are associated with GRTH protein. GRTH also selectively binds mRNAs of pro-apoptotic and anti-apoptotic genes, the death receptor and proteins involved in the NF-kB pathways to mediate anti-apoptotic regulation (Gutti et al., 2008). GRTH is required to maintain the structural integrity of the chromatoid body (storage/processing organelle of mRNAs that contains members of the small miRNA RISC-complex) during spermatogenesis (Sato et al., 2010). GRTH also participates in the regulation of microRNA biogenesis in germ cells (Dai et al., 2011) and associates with polyribosome for translational initiation of target genes. In Leydig cells, GRTH prevents overstimulation of gonadotropin-induced androgen pathway by promoting degradation of StAR protein (Fukushima et al., 2011).
Atlas Image
Model of GRTH action in male germ cells during development (derived from mouse studies). 56 kDa GRTH species enters the nucleus (1), where it binds messages and associates with CRM1 (2) as mRNP complex to export messages through nuclear pores via the CRM1 pathway to the cytoplasm (3a) and to the chromatoid body (CB), either directly (via nuclear pores adjacent to or associated with the CB) (3b) or indirectly via the cytoplasmic route (4b). It is phosphorylated at cytoplasmic sites, and participates in translation at polyribosomes (4a). In the CB, messages are potentially regulated via si/mi/pi RNA pathway (5a and b). Stored messages are subsequently translated in polyribosomes (4a and 6) at specific times during spermatogenesis.
Atlas Image
GRTH is essential for spermatid development and completion of spermatogenesis (derived from studies of GRTH-/- mouse model). Top panel: Diagram of spermatogenic progression. Representative germ cells during spermatogenesis are shown in the diagram above. Cells expressing GRTH are boxed in red. The regulation of gene expression during the developmental process is governed in a precise temporal sequence. Lower panel: I. GRTH dependent expression of proteins. II. Schematic germ-cell development. Unlike the wild type (WT) showing progression to mature sperm, germ cells of GRTH knockout mice fail to elongate at step 8 of round spermatids (RS).

Implicated in

Entity name
Azoospermia
Note
A missense mutation (R242H) in exon 8 identified in 5% of an infertile Japanese patient population with non-obstructive azoospermia (NOA) abrogated the generation of the 61 kDa phosphorylated-GRTH species (Tsai-Morris et al., 2007; Tsai-Morris et al., 2008). A silent mutation located in exon 10 (C1194T, nt) identified in Chinese patients with idiopathic azoospermia was proposed to increase the risk of impaired spermatogenesis (Zhoucun et al., 2006). This could result from its location in the binding motif of splicing factor 2 through affecting pre-RNA splicing of the GRTH gene and ultimately its expression. However, such mutation was not observed in the infertile Japanese patients with non-obstructive azoospermia (Tsai-Morris et al., 2008), which indicated segregration of the mutation to the Chinese population.

Bibliography

Pubmed IDLast YearTitleAuthors
162936492006Single nucleotide polymorphisms of the gonadotrophin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment.A Z et al
220869162011Testis-specific miRNA-469 up-regulated in gonadotropin-regulated testicular RNA helicase (GRTH/DDX25)-null mice silences transition protein 2 and protamine 2 messages at sites within coding region: implications of its role in germ cell development.Dai L et al
216919482011Gonadotropin-regulated testicular helicase (GRTH/DDX25): a master post-transcriptional regulator of spermatogenesis.Dufau ML et al
178895512007Gonadotropin-regulated testicular helicase (GRTH/DDX25): an essential regulator of spermatogenesis.Dufau ML et al
217197032011Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a negative regulator of luteinizing/chorionic gonadotropin hormone-induced steroidogenesis in Leydig cells: central role of steroidogenic acute regulatory protein (StAR).Fukushima M et al
184307332008Gonadotropin-regulated testicular helicase (DDX25), an essential regulator of spermatogenesis, prevents testicular germ cell apoptosis.Gutti RK et al
201760592010Relevance of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) in the structural integrity of the chromatoid body during spermatogenesis.Sato H et al
104289711999Dbp5, a DEAD-box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/Nup159p.Schmitt C et al
169687032006Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is a transport protein involved in gene-specific mRNA export and protein translation during spermatogenesis.Sheng Y et al
106088601999A novel gonadotropin-regulated testicular RNA helicase. A new member of the dead-box family.Tang PZ et al
224793282012Role of gonadotropin regulated testicular RNA helicase (GRTH/Ddx25) on polysomal associated mRNAs in mouse testis.Tsai-Morris CH et al
223314722012Androgen-induced activation of gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) transcription: essential role of a nonclassical androgen response element half-site.Villar J et al

Other Information

Locus ID:

NCBI: 29118
MIM: 607663
HGNC: 18698
Ensembl: ENSG00000109832

Variants:

dbSNP: 29118
ClinVar: 29118
TCGA: ENSG00000109832
COSMIC: DDX25

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000109832ENST00000263576Q9UHL0
ENSG00000109832ENST00000525943Q9UHL0
ENSG00000109832ENST00000525943A0A384NYS3
ENSG00000109832ENST00000526875E9PR46
ENSG00000109832ENST00000530129H0YD26
ENSG00000109832ENST00000530414J3QL17
ENSG00000109832ENST00000584970J3QRJ6
ENSG00000109832ENST00000637851A0A1B0GV69

Expression (GTEx)

0
5
10
15
20
25
30
35

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203786152010Evaluation of 172 candidate polymorphisms for association with oligozoospermia or azoospermia in a large cohort of men of European descent.40
178895512007Gonadotropin-regulated testicular helicase (GRTH/DDX25): an essential regulator of spermatogenesis.20
195360922009Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array.13
198754922010Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25): a multifunctional protein essential for spermatogenesis.12
178484142007Polymorphism of the GRTH/DDX25 gene in normal and infertile Japanese men: a missense mutation associated with loss of GRTH phosphorylation.7
178484142007Polymorphism of the GRTH/DDX25 gene in normal and infertile Japanese men: a missense mutation associated with loss of GRTH phosphorylation.7
162936492006Single nucleotide polymorphisms of the gonadotrophin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment.6
162936492006Single nucleotide polymorphisms of the gonadotrophin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment.6
241680582014Association of the gonadotrophin-regulated testicular RNA helicase gene polymorphism with human male infertility.0

Citation

Chon-Hwa Tsai-Morris ; Maria L Dufau

DDX25 (DEAD (Asp-Glu-Ala-Asp) box helicase 25)

Atlas Genet Cytogenet Oncol Haematol. 2012-02-01

Online version: http://atlasgeneticsoncology.org/gene/46826/ddx25