Alternative titles; symbols
HGNC Approved Gene Symbol: DICER1
SNOMEDCT: 702411003, 782722002;
Cytogenetic location: 14q32.13 Genomic coordinates (GRCh38) : 14:95,086,228-95,158,010 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.13 | GLOW syndrome, somatic mosaic | 618272 | 3 | |
| Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors | 138800 | Autosomal dominant | 3 | |
| Pleuropulmonary blastoma | 601200 | Autosomal dominant | 3 | |
| Rhabdomyosarcoma, embryonal, 2 | 180295 | 3 |
The DICER1 gene, a member of the ribonuclease III (RNaseIII) family, is involved in the generation of microRNAs (miRNAs), which modulate gene expression at the posttranscriptional level (summary by Rio Frio et al., 2011). DICER1 possesses an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus DICER, also known as helicase-MOI, is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression (Matsuda et al., 2000).
Evidence also suggests that DICER1 may act as a haploinsufficient tumor suppressor gene (Bahubeshi et al., 2010; Rio Frio et al., 2011).
To identify proteins interacting with 5-lipoxygenase (ALOX5; 152390), Provost et al. (1999) used a yeast 2-hybrid approach to screen a human lung cDNA library. A 2.1-kb clone contained a partial cDNA of a human protein with high homology to the hypothetical helicase K12H4.8 from C. elegans. Analysis of the predicted amino acid sequence revealed the presence of an RNase III motif and a double-stranded RNA (dsRNA)-binding domain, indicative of a protein of nuclear origin. C. elegans K12H4.8 and the human homolog share 58% identity over 275 amino acids.
Matsuda et al. (2000) isolated a full-length cDNA encoding a gene they called HERNA for 'helicase with RNase motif.' The HERNA cDNA consists of 7,037 basepairs and has a predicted open reading frame encoding 1,924 amino acids. Matsuda et al. (2000) also recognized the homology to C. elegans K12H4.8. HERNA expression was detected by cycle-limited RT-PCR in brain, heart, lung, liver, pancreas, kidney, and placenta, but not in skeletal muscle, suggesting that HERNA may be ubiquitously expressed at variable levels.
Matsuda et al. (2000) used PCR-based monochromosomal somatic cell hybrid mapping to localize the HERNA gene to human chromosome 14. Analysis of radiation hybrid mapping panels refined the localization to 14q31.
Crystal Structure
MacRae et al. (2006) determined the crystal structure of DICER. In an intact DICER enzyme, the PAZ domain, a module that binds the end of dsRNA, is separated from the 2 catalytic RNase III domains by a flat, positively charged surface. The 65-angstrom distance between the PAZ and RNase III domains matches the length spanned by 25 basepairs of RNA. Thus, MacRae et al. (2006) concluded that Dicer itself is a molecular ruler that recognizes dsRNA and cleaves a specified distance from the helical end.
The 21-nucleotide small temporal RNA (stRNA) let7 (605386) regulates developmental timing in C. elegans and probably in other bilateral animals. Hutvagner et al. (2001) presented in vivo and in vitro evidence that in Drosophila, a developmentally regulated precursor RNA is cleaved by an RNA interference-like mechanism to produce mature let7 stRNA. Targeted disruption in cultured human cells of the mRNA encoding the enzyme DICER, which acts in the RNA interference pathway, leads to accumulation of the LET7 precursor. Thus, Hutvagner et al. (2001) concluded that the RNA interference and stRNA pathways intersect. Both pathways require the RNA processing enzyme DICER to produce the active small RNA component that represses gene expression.
In S. pombe, Volpe et al. (2002) deleted the argonaute (AGO1, or EIF2C1; 606228), DICER, and RNA-dependent RNA polymerase gene homologs, which encode part of the machinery responsible for RNA interference. Deletion resulted in the aberrant accumulation of complementary transcripts from centromeric heterochromatic repeats. This was accompanied by transcription of derepression of transgenes integrated at the centromere, loss of histone H3 (see 602810) lysine-9 methylation, and impairment of centromere function. Volpe et al. (2002) proposed that double-stranded RNA arising from centromeric repeats targets formation and maintenance of heterochromatin through RNA interference.
DICER contains 2 domains related to the bacterial double-stranded RNA (dsRNA)-specific endonuclease, RNase III, which functions as a homodimer. Based on an x-ray structure of the Aquifex aeolicus RNase III, Blaszczyk et al. (2001) proposed models of the enzyme interaction with dsRNA and its cleavage at 2 composite catalytic centers. Zhang et al. (2004) generated mutations in human DICER and E. coli RNase III residues implicated in the catalysis and studied their effects on RNA processing. They determined that both enzymes have only 1 processing center that contains 2 RNA cleavage sites and generates products with 2-nucleotide 3-prime overhangs. Zhang et al. (2004) proposed that DICER functions through intramolecular dimerization of its 2 RNase III domains, assisted by the flanking RNA-binding domains, PAZ and dsRBD.
Tomari et al. (2004) showed that in Drosophila, the orientation of the DICER2/R2D2 protein heterodimer on the small interfering RNA (siRNA) duplex determines which siRNA strand associates with the core RNA-induced silencing complex (RISC) protein Argonaute-2 (AGO2, or EIF2C2; 606229). R2D2 binds the siRNA end with the greatest double-stranded character, thereby orienting the heterodimer on the siRNA duplex. Strong R2D2 binding requires a 5-prime-phosphate on the siRNA strand that is excluded from the RISC. Thus, Tomari et al. (2004) concluded that R2D2 is both a protein sensor for siRNA thermodynamic asymmetry and a licensing factor for entry of authentic siRNAs into the RNAi pathway.
AU-rich elements (AREs) in the 3-prime UTRs of unstable mRNAs dictate their degradation. Using an RNA interference-based screen in Drosophila S2 cells, Jing et al. (2005) found that Dicer-1, Ago1, and Ago2, components involved in microRNA (miRNA) processing and function, were required for rapid decay of mRNA containing AREs of tumor necrosis factor-alpha (TNF; 191160). The requirement for Dicer in the instability of ARE-containing mRNA (ARE-RNA) was confirmed in HeLa cells. Jing et al. (2005) showed that miRNA16 (miR16), a human miRNA containing an UAAAUAUU sequence that is complementary to the ARE sequence, was required for ARE-RNA turnover. The role of miR16 in ARE-RNA decay was sequence-specific and required the ARE-binding protein tristetraprolin (TTP, or ZFP36; 190700). TTP did not directly bind miR16, but interacted through association with Ago/EIF2C family members to complex with miR16 and assist in the targeting of ARE. Jing et al. (2005) concluded that miRNA targeting of ARE appears to be an essential step in ARE-mediated mRNA degradation.
Chendrimada et al. (2005) demonstrated that TRBP (605053), which contains 3 double-stranded RNA-binding domains, is an integral component of a Dicer-containing complex. Biochemical analysis of TRBP-containing complexes revealed the association of Dicer-TRBP with AGO2, the catalytic engine of RISC. The physical association of Dicer-TRBP and AGO2 was confirmed after the isolation of the ternary complex using Flag-tagged AGO2 cell lines. In vitro reconstitution assays demonstrated that TRBP is required for the recruitment of AGO2 to the small interfering RNA (siRNA) bound by Dicer. Knockdown of TRBP resulted in destabilization of Dicer and a consequent loss of miRNA biogenesis. Finally, depletion of the Dicer-TRBP complex via exogenously introduced siRNAs diminished RISC-mediated reporter gene silencing. Chendrimada et al. (2005) concluded that these results support a role of the Dicer-TRBP complex not only in miRNA processing but also as a platform for RISC assembly.
Hatfield et al. (2005) reported the necessity of the miRNA pathway for proper control of germline stem cell (GSC) division in Drosophila melanogaster. Analysis of GSCs mutant for dicer-1 (dcr-1), the double-stranded RNaseIII essential for miRNA biogenesis, revealed a marked reduction in the rate of germline cyst production. These dcr-1 mutant GSCs exhibit normal identity but are defective in cell cycle control. On the basis of cell markers and genetic interactions, Hatfield et al. (2005) concluded that dcr-1 mutant GSCs are delayed in the G1 to S transition, which is dependent on the cyclin-dependent kinase inhibitor Dacapo, suggesting that miRNAs are required for stem cells to bypass the normal G1/S checkpoint.
Maniataki and Mourelatos (2005) found that pre-miRNA-fueled assembly of RISC in humans differed from the assembly of RISC by siRNA in Drosophila in terms of the sequence of events, energy requirements, and the final RISC product. In human cells, DICER was associated with AGO2 prior to its encounter with pre-miRNA. The preformed AGO2/DICER-containing complex assembled RISCs from pre-miRNAs but not from siRNA duplexes, and the process was independent of added ATP or GTP. The final RISC product, a ribonucleoprotein made up of AGO2 and miRNA, could be released from DICER.
Gregory et al. (2005) immunoprecipitated approximately 500-kD RISC complexes from human embryonic kidney cells and found that they contained DICER, TRBP, and AGO2. The RISC complex cleaved target RNA using pre-miRNA hairpin as well as duplex siRNA, but it displayed nearly 10-fold greater activity using the pre-miRNA DICER substrate. RISC distinguished the guide strand of the siRNA from the passenger strand and specifically incorporated the guide strand. ATP was not required for miRNA processing, RISC assembly, or multiple rounds of AGO2-mediated target RNA cleavage.
Giraldez et al. (2006) found that zebrafish embryos deficient for maternal and zygotic Dicer activity cannot generate mature miRNAs. These mutants displayed defects during gastrulation and brain morphogenesis that were rescued by injection of processed miRNAs belonging to the miR430 family (homologous to human miR302A, 614596). Giraldez et al. (2006) used a microarray approach and in vivo target validation to determine that miR430 regulates several hundred target mRNA molecules in the zebrafish zygote and embryo. Most targets are maternally expressed mRNAs that accumulate in the absence of miR430. Giraldez et al. (2006) also showed that miR430 accelerated the deadenylation of target mRNAs. They concluded that miR430 facilitates the deadenylation and clearance of maternal mRNAs during early embryogenesis.
Tam et al. (2008) showed that a subset of pseudogenes generates endogenous small interfering RNAs (endo-siRNAs) in mouse oocytes. These endo-siRNAs are often processed from double-stranded RNAs formed by hybridization of spliced transcripts from protein-coding genes to antisense transcripts from homologous pseudogenes. An inverted repeat pseudogene can also generate abundant small RNAs directly. A second class of endo-siRNAs may enforce repression of mobile genetic elements, acting together with Piwi-interacting RNAs. Loss of Dicer, a protein integral to small RNA production, increases expression of endo-siRNA targets, demonstrating their regulatory activity. Tam et al. (2008) concluded that their findings indicated a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute (see 607355)-mediated catalysis in humans.
Using mouse oocytes, Watanabe et al. (2008) demonstrated that endogenous siRNAs are derived from naturally occurring double-stranded RNAs (dsRNAs) and have roles in the regulation of gene expression. By means of deep sequencing, Watanabe et al. (2008) identified a large number of both approximately 25- to 27-nucleotide Piwi-interacting RNAs (piRNAs) and approximately 21-nucleotide siRNAs corresponding to mRNAs or retrotransposons in growing oocytes. piRNAs are bound to Mili (610310) and have a role in the regulation of retrotransposons. siRNAs are exclusively mapped to retrotransposons or other genomic regions that produce transcripts capable of forming double-stranded RNA structures. Inverted repeat structures, bidirectional transcription, and antisense transcripts from various loci are sources of the double-stranded RNAs. Some precursor transcripts of siRNAs are derived from expressed pseudogenes, indicating that one role of pseudogenes is to adjust the level of the founding source mRNA through RNAi. Watanabe et al. (2008) showed that loss of Dicer or Ago2 (606229) resulted in decreased levels of siRNAs and increased levels of retrotransposon and protein-coding transcripts complementary to the siRNAs. Thus, Watanabe et al. (2008) concluded that the RNA interference (RNAi) pathway regulates both protein-coding transcripts and retrotransposons in mouse oocytes. They also concluded that their results revealed a role for endogenous siRNAs in mammalian oocytes and showed that organisms lacking RNA-dependent RNA polymerase (RdRP) activity can produce functional endogenous siRNAs from naturally occurring double-stranded RNAs.
Ghildiyal et al. (2008) independently identified 21-nucleotide endo-siRNAs that corresponded to transposons and heterochromatic sequences in the somatic cells of Drosophila melanogaster. Ghildiyal et al. (2008) also detected endo-siRNAs complementary to mRNAs; these siRNAs disproportionately mapped to the complementary regions of overlapping mRNAs predicted to form double-stranded RNA in vivo. Normal accumulation of somatic endo-siRNAs required the siRNA-generating ribonuclease Dicer2 and the RNA interference effector protein Ago2. Ghildiyal et al. (2008) proposed that endo-siRNAs generated by the fly RNAi pathway silence selfish genetic elements in the soma, much as Piwi-interacting RNAs do in the germline.
Kawamura et al. (2008) showed that in cultured Drosophila S2 cells, AGO2 associated with endogenous small RNAs of 20-22 nucleotides in length, which they had collectively named endogenous short interfering RNAs (esiRNAs). EsiRNAs can be divided into 2 groups: one that mainly corresponds to a subset of retrotransposons, and the other that arises from stem-loop structures. EsiRNAs are produced in a Dicer-2-dependent manner from distinctive genomic loci, are modified at the 3-prime ends, and can direct AGO2 to cleave target RNAs. Mutations in Dicer-2 caused an increase in retrotransposon transcripts. Kawamura et al. (2008) concluded that, together, their findings indicate that different types of small RNAs and Argonautes are used to repress retrotransposons in germline and somatic cells in Drosophila.
Czech et al. (2008) independently showed that Drosophila generated endogenous small interfering RNAs in both gonadal and somatic tissues. Production of these RNAs requires Dicer-2, but a subset depends preferentially on Loquacious (TARBP2; 605053) rather than the canonical Dicer-2 partner, R2D2. EsiRNAs arose both from the convergent transcription units and from structured genomic loci in a tissue-specific fashion. They predominantly join AGO2 and have the capacity, as a class, to target both protein-coding genes and mobile elements. Czech et al. (2008) concluded that these observations expand the repertoire of small RNAs in Drosophila, adding a class that blurs distinctions based on known biogenesis mechanisms and functional roles.
Okamura et al. (2008) reported that siRNAs derived from long hairpin RNA genes (hpRNA) program Slicer complexes that can repress endogenous target transcripts. The Drosophila hpRNA pathway is a hybrid mechanism that combines canonical RNA interference factors Dicer-2, Hen1 (C1ORF59; 612178), and AGO2 with a canonical microRNA factor Loquacious to generate approximately 21-nucleotide siRNAs. Okamura et al. (2008) concluded that these novel regulatory RNAs reveal unexpected complexity in the sorting of small RNAs, and open a window onto the biologic usage of endogenous RNA interference in Drosophila.
Merritt et al. (2008) observed decreased mRNA and protein expression of DICER1 and DROSHA (RNASEN; 608828) in 60 and 51%, respectively, of 111 invasive epithelial ovarian cancer (167000) specimens. Low DICER1 expression was significantly associated with advanced tumor stage (p = 0.007), and low DROSHA expression with suboptimal surgical cytoreduction (p = 0.02). Cancer specimens with both high DICER1 expression and high DROSHA expression were associated with increased median survival. Statistical analysis showed that low DICER1 expression was associated with decreased survival. Although rare missense variants were found in both genes, the presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low DICER1 expression. The findings implicated a component of the RNA-interference machinery, which regulates gene expression, in the pathogenesis of ovarian cancer. Merritt et al. (2009) noted that 109 of the 111 samples used in the 2008 study had serous histologic features, of which 93 were high-grade and 16 low-grade tumors.
By multiple sequence alignment, Forman et al. (2008) identified highly conserved LET7-binding sequences within the coding regions of multiple genes, including DICER. Cotransfection experiments with human embryonic kidney 293 cells revealed that LET7 downregulated an expression vector containing only the DICER coding sequence, which contains 3 LET7-binding sites. Synonymous mutations of these LET7-binding sites permitted DICER expression. Experiments with a human colorectal cancer cell line suggested that processing of LET7 pre-miRNA by DICER was required for downregulation of DICER through its coding sequence in a negative-feedback loop.
Nakagawa et al. (2010) reported that inactivation of the C. elegans Dcr1 gene, which encodes the Dicer ribonuclease important for processing of small RNAs, compromises apoptosis and blocks apoptotic chromosome fragmentation. Dcr1 was cleaved by the Ced3 (601763) caspase to generate a C-terminal fragment with deoxyribonuclease activity, which produced 3-prime hydroxyl DNA breaks on chromosomes and promoted apoptosis. Thus, caspase-mediated activation of apoptotic DNA degradation is conserved. Nakagawa et al. (2010) concluded that Dcr1 functions in fragmenting chromosomal DNA during apoptosis in addition to processing small RNAs, and undergoes a protease-mediated conversion from a ribonuclease to a deoxyribonuclease.
Raaijmakers et al. (2010) demonstrated that deletion of Dicer1 specifically in mouse osteoprogenitors but not in mature osteoblasts disrupts the integrity of hematopoiesis. Myelodysplasia resulted and acute myelogenous leukemia emerged that had acquired several genetic abnormalities while having intact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds (607444), the gene mutated in Shwachman-Bodian-Diamond syndrome (260400), a human bone marrow failure and leukemia predisposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, Raaijmakers et al. (2010) concluded that perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation, and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, Raaijmakers et al. (2010) concluded that primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis.
In mice, Ago2 (EIF2C2; 606229) is uniquely required for viability, and only this Argonaute family member retains catalytic competence. To investigate the evolutionary pressure to conserve Argonaute enzymatic activity, Cheloufi et al. (2010) engineered a mouse with catalytically inactive Ago2 alleles. Homozygous mutants died shortly after birth with an obvious anemia. Examination of microRNAs and their potential targets revealed a loss of miR451 (612071), a small RNA important for erythropoiesis. Though this microRNA is processed by Drosha, its maturation does not require Dicer. Instead, the pre-miRNA becomes loaded into Ago and is cleaved by the Ago catalytic center to generate an intermediate 3-prime end, which is then further trimmed. Cheloufi et al. (2010) concluded that their findings linked the conservation of Argonaute catalysis to a conserved mechanism of microRNA biogenesis that is important for vertebrate development.
Su et al. (2010) showed that TAp63 (603273) suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR130b (613682) to suppress metastasis. Metastatic mouse and human tumors deficient in TAp63 express Dicer at very low levels, and Su et al. (2010) found that modulation of expression of Dicer and miR130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. Su et al. (2010) concluded that their data provided a novel understanding of the roles of TAp63 in tumor and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR130b, and may have implications for the many processes regulated by miRNAs.
Park et al. (2011) reported that human DICER anchors not only the 3-prime end of microRNAs but also the 5-prime end, with the cleavage site determined mainly by the distance (approximately 22 nucleotides) from the 5-prime end (5-prime counting rule). This cleavage requires a 5-prime-terminal phosphate group. Further, Park et al. (2011) identified a novel basic motif (5-prime pocket) in human DICER that recognizes the 5-prime phosphorylated end. The 5-prime counting rule and the 5-prime anchoring residues are conserved in Drosophila Dicer-1, but not in Giardia Dicer. Mutations in the 5-prime pocket reduce processing efficiency and alter cleavage sites in vitro. Consistently, miRNA biogenesis is perturbed in vivo when Dicer-null embryonic stem cells are replenished with the 5-prime-pocket mutant. Thus, Park et al. (2011) concluded that 5-prime end recognition by DICER is important for the precise and effective biogenesis of miRNAs.
Francia et al. (2012) demonstrated in human, mouse, and zebrafish that DICER and DROSHA (608828), but not downstream elements of the RNAi pathway, are necessary to activate the DNA damage response (DDR) upon exogenous DNA damage and oncogene-induced genotoxic stress, as studied by DDR foci formation and by checkpoint assays. DDR foci are sensitive to RNase A treatment, and DICER- and DROSHA-dependent RNA products are required to restore DDR foci in RNase-A-treated cells. Through RNA deep sequencing and the study of DDR activation at a single inducible DNA double-strand break, Francia et al. (2012) demonstrated that DDR foci formation requires site-specific DICER- and DROSHA-dependent small RNAs, named DDRNAs, which act in a MRE11-RAD50-NBS1-complex (see 602667)-dependent manner. DDRNAs, either chemically synthesized or in vitro generated by DICER cleavage, are sufficient to restore the DDR in RNase-A-treated cells, also in the absence of other cellular RNAs.
Kaneko et al. (2011) showed that DICER1 is reduced in the retinal pigment epithelium (RPE) of humans with geographic atrophy (see 603075) and that conditional ablation of DICER1, but not of 7 other microRNA processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induced accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA was increased in the RPE of humans with geographic atrophy, and this pathogenic RNA induced human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevented DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA could not induce RPE degeneration in mice. Kaneko et al. (2011) concluded that their findings revealed an miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, showed that Alu RNA can directly cause human pathology, and identified new targets for a major cause of blindness.
Using mouse and human RPE cells and mice lacking various genes, Tarallo et al. (2012) showed that a DICER1 deficit or Alu RNA exposure activated the NLRP3 (606416) inflammasome, triggering Toll-like receptor-independent MYD88 (602170) signaling via IL18 (600953) in the RPE. Inhibition of inflammasome components, MYD88, or IL18 prevented RPE degeneration induced by DICER1 loss or Alu RNA exposure. Because RPE in human geographic atrophy contained elevated NLRP3, PYCARD (606838), and IL18, Tarallo et al. (2012) suggested targeting this pathway for prevention and/or treatment of geographic atrophy.
Li et al. (2013) showed that infection of hamster cells and suckling mice by Nodamura virus, a mosquito-transmissible RNA virus, requires RNA interference suppression by its B2 protein. Loss of B2 expression or its suppressor activity leads to abundant production of viral siRNAs and rapid clearance of the mutant viruses in mice. However, viral small RNAs detected during virulent infection by Nodamura virus do not have the properties of canonical siRNAs. Maillard et al. (2013) demonstrated that undifferentiated mouse cells infected with encephalomyocarditis virus or Nodamura virus accumulate approximately 22-nucleotide RNAs with all the signature features of siRNAs. These derive from viral double-strand RNA (dsRNA) replication intermediates, incorporate into Ago2 (606229), are eliminated in Dicer knockout cells, and decrease in abundance upon cell differentiation. Furthermore, genetically ablating a Nodamura virus-encoded suppressor of RNAi that antagonizes Dicer during authentic infections reduces Nodamura virus accumulation, which is rescued in RNAi-deficient mouse cells. Maillard et al. (2013) concluded that antiviral RNA interference operates in mammalian cells. Li et al. (2013) concluded that their findings and those of Maillard et al. (2013) illustrated that Dicer-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by 2 distinct positive-strand RNA viruses.
In mice, Dias et al. (2014) showed that beta-catenin (CTNNB1; 116806) mediates proresilient and anxiolytic effects in the nucleus accumbens, mediated by D2-type medium spiny neurons. Using genomewide beta-catenin enrichment mapping, Dias et al. (2014) identified Dicer1 as a beta-catenin target gene that mediates resilience. Small RNA profiling after excising beta-catenin from nucleus accumbens in the context of chronic stress revealed beta-catenin-dependent microRNA regulation associated with resilience. Dias et al. (2014) concluded that these findings established beta-catenin as a critical regulator in the development of behavioral resilience, activating a network that includes DICER1 and downstream microRNAs. The authors stated that this evidence presented a foundation for the development of novel therapeutic targets to promote stress resilience.
Copy Number Variation in Cancer
By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA express. They also found a high frequency of copy number abnormalities of DICER1, AGO2 (606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.
Pleuropulmonary Blastoma
Hill et al. (2009) demonstrated 10 loss-of-function and 1 missense mutation in the DICER1 gene (see, e.g., 606241.0001-606241.0005) leading to pleuropulmonary blastoma (PPB; 601200). In patients with tumors, there was loss of the wildtype allele within malignant areas in 6 of 7 the cases.
Bahubeshi et al. (2010) reported 2 unrelated families with cystic nephroma with or without PPB associated with different heterozygous mutations in the DICER1 gene in each family (see, e.g., 606241.0006). The findings added cystic nephroma to the phenotypic spectrum of PPB. Loss of heterozygosity at the DICER1 locus was not observed in tumor tissue. No germline DICER1 mutations were found in 50 children with Wilms tumor.
Cervical Embryonal Rhabdomyosarcoma
Foulkes et al. (2011) stated that 40 different heterozygous germline mutations in DICER1 had been reported worldwide in 42 probands who developed pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian sex cord-stromal tumors, or multinodular goiter as children or young adults. Foulkes et al. (2011) reported DICER1 mutations in 7 additional families manifesting uterine cervix embryonal rhabdomyosarcoma (CERMS, 4 cases), primitive neuroectodermal tumor (CPNET, 1 case), Wilms tumor (3 cases), pulmonary sequestration (1 case), and juvenile intestinal polyp (1 case). One mutation carrier in 1 family had complex cardiac defects, including transposition of the great arteries, bicuspid pulmonary valve, atrial septal defect, and small patent ductus arteriosus, and a mutation carrier in another family had pulmonary sequestration. Examination of tumor tissue from several patients did not show loss of heterozygosity for DICER1, indicating that some different second events must be required for tumor formation. However, the findings indicated that germline DICER1 mutations serve as a conditioning context for the development of multiple tumor types.
Multinodular Goiter 1, with or without Sertoli-Leydig Cell Tumors
In affected members of 5 unrelated families with autosomal dominant multinodular goiter with or without Sertoli-Leydig cell tumors (MNG1; 138800), Rio Frio et al. (2011) identified 5 different heterozygous mutations in the DICER1 gene (see, e.g., 606241.0007-606241.0010). Four of the families had previously been reported by O'Brien and Wilansky (1981), Niedziela (2008), Bignell et al. (1997), and Druker et al. (1997). Studies of both types of tumors from several families showed no loss of heterozygosity at the DICER1 locus. Goiter tissue showed mixed immunostaining results, with some tissues showing no DICER1 protein staining and other tissues showing clear cytoplasmic staining. RNA studies from patient lymphoblasts showed perturbations of miRNA compared to controls, suggesting a dysregulation of gene expression patterns. In particular, LET7A (605386) and miR345 were both decreased in DICER1-related goiter tissue.
Pineoblastoma
Sabbaghian et al. (2012) reported a single patient with a highly aggressive pineoblastoma due to germline frameshift mutation in DICER1. This tumor had loss of heterozygosity with loss of function of the wildtype allele of DICER1. Interestingly, it is possible for a tumor to survive without any DICER1 activity.
Wilms Tumor
Rakheja et al. (2014) reported the whole-exome sequencing of 44 Wilms tumors (see WT1, 194070), identifying missense mutations in the microRNA (miRNA)-processing enzymes DROSHA (608828) and DICER1, and novel mutations in MYCN (164840), SMARCA4 (603254), and ARID1A (603024). Examination of tumor miRNA expression, in vitro processing assays, and genomic editing in human cells demonstrated that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5-prime arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumor-suppressing miRNAs, including the LET7 family (see 605386), which are important regulators of MYCN, LIN28 (see 611043), and other Wilms tumor oncogenes. Rakheja et al. (2014) concluded that these results provided insights into the mechanisms through which mutations in miRNA biogenesis components reprogram miRNA expression in human cancer and suggested that these defects define a distinct subclass of Wilms tumors.
Palculict et al. (2016) identified 2 different heterozygous germline mutations in the DICER1 gene in affected members from 2 unrelated families with familial Wilms tumors. Eleven individuals in 1 family carried a heterozygous G803R mutation that was identified by whole-genome sequencing and confirmed by Sanger sequencing. Four individuals in this family had Wilms tumor, diagnosed between 38 and 57 months of age. Tumor tissue available from 1 patient showed homozygosity for the G803R mutation and loss of heterozygosity at the DICER1 locus. Some individuals in this family had phenotypes of so-called DICER1 syndrome, including cysts in the thyroid, lung, and kidney. The proband from the second family with Wilms tumor carried a heterozygous frameshift mutation (Arg800fsTer5) that was identified by direct sequencing of the DICER1 gene in 47 families. Tumor samples were not available from the second family. Penetrance appeared to be incomplete.
GLOW Syndrome
In 2 unrelated patients with developmental delay, overgrowth, bilateral cystic lung lesions, and Wilms tumor (GLOW; 618272), Klein et al. (2014) detected 2 missense mutations in the DICER1 gene (606241.0013 and 606241.0014) present in the mosaic state. Tissue abundance of the mutated DICER DNA ranged from 21 to 37% in patient 1 and 28 to 47% in patient 2 in blood, tumor, and unaffected kidney samples.
MicroRNAs have a central role in the development of plants, nematodes, and flies. These miRNAs are produced by the Dicer1 enzyme, which is conserved from fungi to vertebrates. To study its role in vertebrate development, Wienholds et al. (2003) cloned the zebrafish dicer1 ortholog and applied a method for target-selected gene inactivation. They observed an initial build-up of miRNA levels, produced by maternal Dicer1, in homozygous dicer1 mutants, but miRNA accumulation stopped after a few days. This resulted in developmental arrest around day 10. The results indicated that miRNA-producing Dicer1 is essential for vertebrate development.
Bernstein et al. (2003) disrupted the Dicer1 gene in mice. Loss of Dicer1 led to lethality early in development, with Dicer1-null embryos depleted of stem cells. Coupled with the inability to generate viable Dicer1-null embryonic stem (ES) cells, this suggested a role for Dicer and, by implication, the RNAi machinery in maintaining the stem cell population during early mouse development.
By conditional gene targeting, Kanellopoulou et al. (2005) disrupted the Dicer1 gene in mouse ES cells. Dicer-null ES cells were viable, despite being completely defective in RNA interference and generation of microRNAs. However, mutant ES cells displayed severe defects in differentiation both in vitro and in vivo. Epigenetic silencing of centromeric repeat sequences and expression of homologous small dsRNAs were markedly reduced. Reexpression of Dicer in knockout cells rescued these phenotypes. Kanellopoulou et al. (2005) concluded that Dicer participates in multiple, fundamental biologic processes, ranging from stem cell differentiation to maintenance of centromeric heterochromatin structure and centromeric silencing.
Yi et al. (2006) cloned more than 100 miRNAs from skin and showed that epidermis and hair follicles differentially express discrete miRNA families. To explore the functional significance of this finding, they conditionally targeted Dicer1 gene ablation in embryonic skin precursors. Within the first week after loss of miRNA expression, cell fate specification and differentiation were not markedly impaired, and in the interfollicular epidermis, apoptosis was not markedly increased. Notably, however, developing hair germs evaginated rather than invaginated, thereby perturbing the epidermal organization. Thus, Yi et al. (2006) characterized miRNAs in skin, the existence of which was hitherto unappreciated, and demonstrated their differential expression and importance in the morphogenesis of epithelial tissues within this vital organ.
Muljo et al. (2005) found that conditional deletion of the mouse Dcr1 gene in the T-cell lineage resulted in impaired T-cell development and aberrant T-helper (Th) cell differentiation and cytokine production. Deletion of Dcr1 in thymus led to a severe block in CD8 (see 186910)-positive T-cell development and reduced CD4 (186940)-positive T-cell numbers. The CD4-positive cells were defective in miRNA processing and, upon stimulation, proliferated poorly and underwent increased apoptosis. Dcr1-deficient Th cells preferentially expressed Ifng (147570), characteristic of helper cells of the Th1 lineage. Th2 cells lacking Dcr1 failed to silence Ifng expression. Muljo et al. (2005) proposed that the RNAi pathway may participate in epigenetic silencing of relevant genes during Th-cell lineage commitment.
Wang et al. (2006) demonstrated that an RNA interference pathway protects adult flies from infection by 2 evolutionarily diverse viruses. Their work also described a molecular framework for the viral immunity, in which viral double-stranded RNA produced during infection acts as the pathogen trigger whereas Drosophila Dicer-2 and Argonaute-2 (606228) act as host sensor and effector, respectively. Wang et al. (2006) concluded that their findings established a Drosophila model for studying the innate immunity against viruses in animals.
Drosophila have 2 Dicer genes: Dcr1, which controls production of miRNA, and Dcr2, which controls production of siRNA. Galiana-Arnoux et al. (2006) found that Drosophila with a loss-of-function function mutation in Dcr2 were more susceptible to 3 different families of RNA viruses. The viral protein B2, a potent inhibitor of processing of double-stranded RNA, was required for infection and killing of Drosophila. Galiana-Arnoux et al. (2006) concluded that RNA interference mechanisms are important in controlling virus replication in Drosophila.
Murchison et al. (2007) reported that targeted disruption of Dicer in mouse oocytes led to arrest in meiosis I with multiple disorganized spindles and severe chromosome congression defects.
To assess the role of miRNAs in cardiac development, Zhao et al. (2007) deleted Dicer in mouse heart. Mutant mice exhibited embryonic lethality by day 12.5, revealing an essential role for miRNA function in developing heart.
Using gene-trap methods, Otsuka et al. (2007) obtained mice functionally deficient in Dicer1 that did not undergo embryonic lethality due to hypomorphic Dicer1 expression. Analysis of viral growth in peritoneal macrophages of these mice revealed susceptibility to vesicular stomatitis virus (VSV) and herpes simplex-1 virus, but not to other viruses tested. Susceptibility to VSV was not due to increased VSV cell entry nor to deficiencies in type I interferon (e.g., IFNA; 147660) production or IFN responses. Reporter gene analysis of a mouse macrophage cell line transfected with plasmids containing VSV sequences showed that miR24 (see 609705) and miR93 (612984), which were expressed in the both the cell line and in peritoneal macrophages, targeted VSV genes encoding a viral RNA-dependent polymerase and a polymerase cofactor, respectively. Further analysis indicated that miR24 and miR93 suppressed VSV propagation in mouse macrophages. VSV lacking the miR24 and miR93 target sites was more pathogenic in wildtype mice than wildtype VSV. Otsuka et al. (2007) concluded that impairment of miR24 and miR93 production due to Dicer1 deficiency results in increased susceptibility to VSV.
Cuellar et al. (2008) created transgenic mice with targeted ablation of the Dicer1 gene in postmitotic dopaminoceptive neurons and found that the mice developed ataxia, front and hind limb clasping, and decreased life span with death occurring between 10 to 12 weeks of age. Postmortem examination showed reduced brain size, a reduction in miRNAs in the striatum, and smaller striatal neurons. The striatum showed astrogliosis but not neurodegeneration or neuronal loss.
Kobayashi et al. (2008) found that targeted deletion of Dicer1 in mouse cartilage resulted in progressive reduction in the proliferating pool of chondrocytes, leading to severe skeletal growth defects and premature death. Reduction of proliferating chondrocytes in Dicer1-null growth plates was caused by both decreased chondrocyte proliferation and accelerated differentiation into postmitotic hypertrophic chondrocytes.
Koralov et al. (2008) conditionally deleted Dicer in mouse early B-cell progenitors and observed a block in the pro- to pre-B cell transition. Gene expression profiling identified an miR17-92 (see 609416) signature in the 3-prime UTRs of genes upregulated in Dicer -/- pro-B cells, such as Bim (BCL2L11; 603827). Ablation of Bim or transgenic expression of Bcl2 (151430) partially rescued B-cell development. Dicer deficiency had no detectable effect on the developmental V(D)J recombination program, but it did affect antibody diversification by increasing the diversity of Ig-kappa variable regions through increased N sequence insertion and changing Dh element usage in the variable regions of IgH chains.
Chen et al. (2008) generated mice with cardiac-specific knockout of Dicer and observed rapidly progressive dilated cardiomyopathy (CMD; see 115200), heart failure, and postnatal lethality. Dicer-mutant mice showed misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicated significantly reduced heart rates and decreased fractional shortening of Dicer-mutant hearts. Dicer expression was also found to be decreased in failing human hearts in end-stage CMD, and a significant increase in Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Chen et al. (2008) concluded that DICER and miRNAs have critical roles in normal cardiac function and under pathologic conditions.
Friedman et al. (2009) conditionally deleted Dicer in mouse inner ear sensory epithelium hair cells and in nonsensory supporting cells after their normal differentiation from progenitor cells. Removal of Dicer from sensory epithelium, which initially developed normally, caused abnormal growth and subsequent degeneration of mechanosensory hair cells, leading to deafness.
Using a conditional deletion approach, Dugas et al. (2010) generated mice lacking Dicer in oligodendrocytes and oligodendrocyte precursor cells. These mice developed a shivering phenotype that was associated with defects in myelination. Microarray analysis identified Mir219 (see MIR219-1; 611500), Mir138 (see MIR138-1; 613394), and Mir338 (614059) as the most highly induced miRNAs during oligodendrocyte differentiation.
Independently, Zhao et al. (2010) created mice lacking Dicer in oligodendrocyte lineage cells. Mutant mice were obtained at a mendelian ratio, but they developed severe tremor and ataxia due to myelinating defects and died around postnatal week 3. Microarray analysis revealed significantly reduced Mir219 and Mir338 expression in both Dicer-knockout and Olig1 (606385)-knockout oligodendrocytes.
Hebert et al. (2010) showed that absence of Dicer in the adult mouse forebrain was accompanied by a mixed neurodegenerative phenotype. Although neuronal loss was observed in the hippocampus, cellular shrinkage was predominant in the cortex. Neuronal degeneration coincided with the hyperphosphorylation of endogenous tau (157140) at several epitopes associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 (MAPK3; 601795) as one of the candidate kinases responsible for this event in vivo. In addition, miRNAs belonging to the miR15 (609703) family were potent regulators of ERK1 expression in mouse neuronal cells and coexpressed with ERK1/2 in vivo. Finally, miR15a was specifically downregulated in Alzheimer disease (104300) brain. The authors hypothesized that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation.
In a family with 3 individuals affected with pleuropulmonary blastoma (PPB; 601200) or lung cysts, Hill et al. (2009) identified a heterozygous T-to-G transversion at nucleotide 4930 in exon 23 of the DICER1 gene, resulting in a leu-to-arg substitution at codon 1583 (L1583R). The mutation affected an evolutionarily conserved amino acid. The nonpolar-to-polar change was not a previously reported sequence variant, nor was it detected in 360 cancer-free controls.
In a family with 3 affected individuals, 1 with pleuropulmonary blastoma (PPB; 601200), 1 with lung cysts, and 1 with cystic nephroma, Hill et al. (2009) identified a heterozygous G-to-T transversion at nucleotide 1689 in exon 9 of DICER1, resulting in a glu-to-ter substitution at codon 493 (E493X). This mutation was associated with a reduced amount of mutant RNA and a loss of DICER1 staining in tumor-associated epithelium.
In a family with pleuropulmonary blastoma (PPB; 601200), Hill et al. (2009) identified a heterozygous C-to-T transition at nucleotide 3012 in exon 18 of DICER1, resulting in an arg-to-ter substitution at codon 934 (R934X). Loss of DICER1 staining in tumor-associated epithelium was identified by immunohistochemistry.
In a family with 2 affected individuals, 1 with pleuropulmonary blastoma (PPB; 601200) and the other with lung cysts, Hill et al. (2009) identified a heterozygous frameshift mutation resulting from insertion of an adenine at position 2574 in exon 15 of the DICER1 gene, resulting in a frameshift starting at codon 788 (T788Nfs). There was a reduced amount of mutant RNA from cell lines containing this mutation.
In a family with pleuropulmonary blastoma (PPB; 601200), Hill et al. (2009) identified a heterozygous C-to-T transition at nucleotide 1812 in exon 10 of the DICER1 gene, resulting in an arg-to-ter substitution at codon 534 (R534X). This mutation was associated with loss of DICER1 staining in tumor-associated epithelium.
In a girl with pleuropulmonary blastoma (PPB; 601200) and cystic nephroma, Bahubeshi et al. (2010) identified a heterozygous 5477C-A transversion in exon 25 of the DICER1 gene, resulting in a ser1826-to-ter (S1826X) substitution that would exclude the double-stranded RNA-binding domain. The patient died at age 5 years. Her brother, who also carried the mutation, had cystic nephroma without PPB and was alive at age 5 years. Heterozygosity for the mutation was also found in the mother, who had goiter (MNG1; 138800) and in 2 unaffected sisters of the proband. There were 2 other maternal relatives with goiter, but DNA was not studied. In cystic nephroma tissue derived from the brother, there was no loss of heterozygosity at the DICER1 locus, but there was decreased immunostaining for the protein in renal tubules. The findings indicated that nephroma can be a part of the PPB spectrum and also illustrated that DICER1 mutations can predispose to goiter.
In 4 members of a family with multinodular goiter with or without Sertoli-Leydig cell tumors (MNG1; 138800), Rio Frio et al. (2011) identified a heterozygous 4-bp deletion (871delAAAG) in the DICER1 gene, resulting in a frameshift and premature termination. A mutant mRNA could not be detected due to nonsense-mediated mRNA decay. The family had originally been reported by O'Brien and Wilansky (1981). The female proband had multinodular goiter at age 16 years and an ovarian Sertoli-Leydig cell tumor at age 18; 3 additional family members with the mutation had multinodular goiter only. Studies of the ovarian tumor showed no loss of heterozygosity for the DICER1 locus.
In 3 affected members of a family with multinodular goiter with or without Sertoli-Leydig cell tumors (MNG1; 138800), Rio Frio et al. (2011) identified a heterozygous 2457C-G transversion in exon 16 of the DICER1 gene, resulting in a de novo splice site and an in-frame deletion of the first 21 bps of exon 16 (2437_2457del21). The mutant transcript generates a predicted DICER1 protein lacking amino acids ile813 to tyr819, resulting in an altered PAZ structure. The family had previously been reported by Niedziela (2008). The proband developed multinodular goiter at age 9 years and an ovarian Sertoli-Leydig cell tumor at age 14. Two other family members developed multinodular goiter only at ages 12 and 17, respectively. There was no loss of heterozygosity at the DICER1 locus in tumor tissue, and immunohistochemical studies showed loss of protein staining in the goiter, intense staining in Sertoli cells, and weak staining in Leydig cells.
In a large Canadian family with multinodular goiter without Sertoli-Leydig cell tumors (MNG1; 138800) reported by Bignell et al. (1997), Rio Frio et al. (2011) identified a heterozygous 2916C-T transition in the DICER1 gene, resulting in a ser839-to-phe (S839F) substitution in a highly conserved residue and predicted to disrupt an alpha-helix in the PAZ domain. The mutation was not found in 455 controls. The mutation was found in all 20 affected individuals and in none of 10 unaffected family members. There was no loss of heterozygosity at the DICER1 locus in tumor tissues analyzed.
In a large Canadian family with multinodular goiter (MNG1; 138800) originally reported by Druker et al. (1997), Rio Frio et al. (2011) identified a heterozygous G-to-T transversion in intron 17 of the DICER1 gene, affecting a splice site and resulting in an in-frame deletion of exon 18, eliminating part of the PAZ domain. The mutation was not seen in 430 controls.
In a family in which the proband had a cervical embryonal rhabdomyosarcoma (CERMS; see 180295) and multinodular goiter (see 138800), Foulkes et al. (2011) identified a heterozygous mutation in exon 21 of the DICER1 gene, a 2-basepair deletion (c.3907_3908delCT) that resulted in frameshift and premature termination (Leu1303ValfsTer4). Other mutation carriers in the family had multinodular goiter, lung cysts, esophageal hamartomatous polyp, and/or thyroid nodule.
In a family in which 2 members had cervical embryonal rhabdomyosarcoma (CERMS; see 180295), Foulkes et al. (2011) identified a heterozygous indel mutation in exon 21 of the DICER1 gene (c.3611_3616delACTACAinsT) that resulted in frameshift and premature termination (Tyr1204LeufsTer29). The proband had lung cysts and multinodular goiter in addition to CERMS; other mutation carriers in the family had Sertoli-Leydig cell tumor, multinodular goiter, and pleomorphic sarcoma.
In a boy with global developmental delay, lung cysts, overgrowth, and Wilms tumor (GLOW; 618272), Klein et al. (2014) identified a heterozygous A-to-T transversion at nucleotide 5138 of the DICER1 gene resulting in a valine substitution for the aspartic acid at codon 1713 (D1713V). Aspartic acid-1713 is highly conserved through evolution, and the mutation in this patient is 13 bp from the mutation in the second patient identified by the authors (606241.0014), which occurred at a known metal binding site essential for DICER1 RNase IIIb domain function. The mutation was identified by whole-exome sequencing of DNA from peripheral mononuclear blood cells. The mutation occurred as a postzygotic event as it was absent from both parents and present in varying abundance in different tissues. Klein et al. (2014) stated that the variant was absent from the EVS database and UCLA clinical genomics dataset. Hamosh (2018) noted that the variant was not present in the gnomAD database (December 30, 2018).
In a boy with global developmental delay, lung cysts, overgrowth, and Wilms tumor (GLOW; 618272), Klein et al. (2014) identified a heterozygous G-to-T transversion at nucleotide 5125 of the DICER1 gene, resulting in an aspartic acid-to-tyrosine substitution at codon 1709 (D1709Y). The aspartic acid at position 1709 is highly conserved and functions as part of a metal binding site essential for 5-prime microRNA cleavage from mature pre-microRNAs and a hotspot for somatic mutations in cancers. Hamosh (2018) noted that the variant was not present in the gnomAD database (December 30, 2018).
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