Mutagenetix > Incidental Mutation

Incidental Mutation 'R0032:Dicer1'

15284

Institutional Source

Beutler Lab

Gene Symbol

Dicer1

Ensembl Gene

ENSMUSG00000041415

Gene Name

dicer 1, ribonuclease type III

Synonyms

D12Ertd7e, Dicer1, 1110006F08Rik

MMRRC Submission

038326-MU

Accession Numbers

Essential gene?

Essential (E-score: 1.000) question?

Stock #

R0032 (G1) of strain 731

Quality Score

Status

Validated

Chromosome

Chromosomal Location

104654001-104718211 bp(-) (GRCm39)

Type of Mutation

nonsense

DNA Base Change (assembly)

A to T at 104671057 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Leucine to Stop codon at position 995 (L995*)

Ref Sequence

ENSEMBL: ENSMUSP00000043676 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000041987]

AlphaFold

no structure available at present

Predicted Effect

probably null
Transcript: ENSMUST00000041987
AA Change: L995*

SMART Domains

Protein: ENSMUSP00000043676
Gene: ENSMUSG00000041415
AA Change: L995*

Domain	Start	End	E-Value	Type
DEXDc	30	233	5.14e-24	SMART
low complexity region	403	419	N/A	INTRINSIC
HELICc	449	546	3.15e-10	SMART
Pfam:Dicer_dimer	620	707	1.4e-25	PFAM
low complexity region	713	723	N/A	INTRINSIC
PAZ	881	1056	1.67e-48	SMART
Blast:PAZ	1080	1129	2e-8	BLAST
RIBOc	1285	1582	1.83e-35	SMART
RIBOc	1665	1831	5.97e-49	SMART
DSRM	1834	1897	6.89e-9	SMART

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000222115

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000222519

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000222528

Meta Mutation Damage Score

0.9755

Coding Region Coverage

1x: 80.9%
3x: 73.4%
10x: 52.4%
20x: 32.5%

Validation Efficiency

94% (87/93)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein possessing an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus. The encoded protein functions as a ribonuclease and is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2010]
PHENOTYPE: Mutation of this locus results in arrest of early embryonic development. [provided by MGI curators]

Allele List at MGI

All alleles(25) : Targeted(14) Gene trapped(11)

Other mutations in this stock

Total: 40 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Acss3	T	A	10: 106,959,156 (GRCm39)	T97S	probably benign	Het
Adcy1	T	C	11: 7,094,729 (GRCm39)	S552P	possibly damaging	Het
C2cd3	T	A	7: 100,093,652 (GRCm39)		probably benign	Het
Cd86	A	T	16: 36,441,235 (GRCm39)	S77R	probably damaging	Het
Cfap54	C	T	10: 92,768,559 (GRCm39)	R188H	probably benign	Het
Cpne8	T	A	15: 90,453,771 (GRCm39)		probably benign	Het
Ctsg	T	A	14: 56,339,196 (GRCm39)	I21F	probably damaging	Het
Cyp2j9	T	G	4: 96,457,043 (GRCm39)	N476T	possibly damaging	Het
Dcaf4	G	A	12: 83,582,762 (GRCm39)		probably benign	Het
Dennd4c	T	C	4: 86,746,387 (GRCm39)		probably null	Het
Dnah10	A	G	5: 124,877,955 (GRCm39)	K2623R	possibly damaging	Het
Dnajc21	G	T	15: 10,461,963 (GRCm39)	T146K	probably benign	Het
Dnmbp	A	C	19: 43,891,158 (GRCm39)	L203R	probably damaging	Het
Eif4g1	C	T	16: 20,504,648 (GRCm39)	S829F	probably damaging	Het
Enkur	T	C	2: 21,194,115 (GRCm39)	I153V	probably benign	Het
Erf	T	C	7: 24,944,500 (GRCm39)	Y277C	possibly damaging	Het
Fcsk	G	A	8: 111,618,735 (GRCm39)	T341M	possibly damaging	Het
Fstl5	T	A	3: 76,555,742 (GRCm39)		probably benign	Het
Grm3	A	G	5: 9,561,452 (GRCm39)		probably null	Het
Il11ra1	A	G	4: 41,768,187 (GRCm39)	E366G	probably damaging	Het
Ipo8	A	G	6: 148,712,209 (GRCm39)	C261R	probably damaging	Het
Itga11	T	C	9: 62,681,377 (GRCm39)	F998L	probably benign	Het
Krt74	T	A	15: 101,669,887 (GRCm39)		noncoding transcript	Het
Me2	T	G	18: 73,927,596 (GRCm39)	M219L	probably benign	Het
Mlh3	A	G	12: 85,292,523 (GRCm39)		probably benign	Het
Nfx1	T	A	4: 41,015,321 (GRCm39)	V842E	probably benign	Het
Oma1	T	A	4: 103,223,209 (GRCm39)	S465T	possibly damaging	Het
Opa1	A	T	16: 29,433,887 (GRCm39)	H574L	probably damaging	Het
Pcsk5	T	C	19: 17,542,179 (GRCm39)	N804S	possibly damaging	Het
Pde4a	C	A	9: 21,112,728 (GRCm39)		probably benign	Het
Pilra	T	A	5: 137,829,527 (GRCm39)	D179V	probably damaging	Het
Piwil1	G	A	5: 128,820,344 (GRCm39)	S247N	probably benign	Het
Prss58	T	G	6: 40,872,633 (GRCm39)	T158P	probably benign	Het
Slc35e3	T	C	10: 117,580,837 (GRCm39)	M156V	probably benign	Het
Slit2	G	A	5: 48,414,198 (GRCm39)	R938Q	probably damaging	Het
Syt8	T	C	7: 141,992,926 (GRCm39)	V152A	probably benign	Het
Tppp2	G	T	14: 52,156,866 (GRCm39)	R81L	possibly damaging	Het
Trpc3	A	G	3: 36,698,405 (GRCm39)	I618T	probably damaging	Het
Zc3h4	T	A	7: 16,168,565 (GRCm39)	D891E	unknown	Het
Zfp120	A	T	2: 149,959,512 (GRCm39)	V270E	possibly damaging	Het

Other mutations in Dicer1

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL00943:Dicer1	APN	12	104,663,031 (GRCm39)	missense	possibly damaging	0.93
IGL01061:Dicer1	APN	12	104,672,586 (GRCm39)	missense	probably null	0.75
IGL01527:Dicer1	APN	12	104,657,869 (GRCm39)	nonsense	probably null
IGL01597:Dicer1	APN	12	104,671,469 (GRCm39)	nonsense	probably null
IGL01636:Dicer1	APN	12	104,688,500 (GRCm39)	missense	probably damaging	1.00
IGL01717:Dicer1	APN	12	104,669,046 (GRCm39)	nonsense	probably null
IGL01765:Dicer1	APN	12	104,672,999 (GRCm39)	missense	probably damaging	1.00
IGL01871:Dicer1	APN	12	104,670,439 (GRCm39)	missense	probably damaging	1.00
IGL02316:Dicer1	APN	12	104,668,812 (GRCm39)	missense	probably damaging	1.00
IGL02317:Dicer1	APN	12	104,663,279 (GRCm39)	missense	probably damaging	1.00
IGL02539:Dicer1	APN	12	104,663,294 (GRCm39)	missense	probably damaging	0.97
IGL02544:Dicer1	APN	12	104,681,091 (GRCm39)	missense	probably damaging	1.00
IGL02664:Dicer1	APN	12	104,671,388 (GRCm39)	missense	probably damaging	1.00
IGL02667:Dicer1	APN	12	104,681,165 (GRCm39)	missense	probably damaging	1.00
IGL03353:Dicer1	APN	12	104,679,366 (GRCm39)	missense	probably damaging	1.00
IGL03377:Dicer1	APN	12	104,678,456 (GRCm39)	missense	probably damaging	0.98
everest	UTSW	12	104,671,387 (GRCm39)	missense	probably damaging	1.00
PIT4480001:Dicer1	UTSW	12	104,662,803 (GRCm39)	missense	probably benign
R0032:Dicer1	UTSW	12	104,671,057 (GRCm39)	nonsense	probably null
R0219:Dicer1	UTSW	12	104,658,384 (GRCm39)	critical splice donor site	probably null
R0242:Dicer1	UTSW	12	104,668,710 (GRCm39)	missense	probably benign	0.02
R0242:Dicer1	UTSW	12	104,668,710 (GRCm39)	missense	probably benign	0.02
R0385:Dicer1	UTSW	12	104,670,433 (GRCm39)	missense	probably damaging	1.00
R0402:Dicer1	UTSW	12	104,697,323 (GRCm39)	missense	probably benign	0.04
R0426:Dicer1	UTSW	12	104,668,801 (GRCm39)	missense	probably damaging	1.00
R0453:Dicer1	UTSW	12	104,668,889 (GRCm39)	missense	probably benign
R0502:Dicer1	UTSW	12	104,671,319 (GRCm39)	missense	probably damaging	1.00
R0507:Dicer1	UTSW	12	104,657,917 (GRCm39)	missense	probably damaging	1.00
R0511:Dicer1	UTSW	12	104,669,100 (GRCm39)	missense	possibly damaging	0.95
R0523:Dicer1	UTSW	12	104,668,750 (GRCm39)	missense	probably damaging	1.00
R0559:Dicer1	UTSW	12	104,672,560 (GRCm39)	missense	probably damaging	1.00
R0600:Dicer1	UTSW	12	104,673,123 (GRCm39)	missense	probably damaging	1.00
R0707:Dicer1	UTSW	12	104,673,144 (GRCm39)	missense	probably damaging	1.00
R1225:Dicer1	UTSW	12	104,657,866 (GRCm39)	missense	probably damaging	0.98
R1351:Dicer1	UTSW	12	104,695,401 (GRCm39)	missense	probably damaging	0.99
R1449:Dicer1	UTSW	12	104,695,502 (GRCm39)	missense	possibly damaging	0.85
R1575:Dicer1	UTSW	12	104,688,228 (GRCm39)	critical splice donor site	probably null
R1642:Dicer1	UTSW	12	104,679,415 (GRCm39)	missense	probably damaging	1.00
R1651:Dicer1	UTSW	12	104,675,064 (GRCm39)	missense	probably damaging	1.00
R1658:Dicer1	UTSW	12	104,666,673 (GRCm39)	missense	probably benign
R1815:Dicer1	UTSW	12	104,688,410 (GRCm39)	missense	probably damaging	1.00
R1816:Dicer1	UTSW	12	104,688,410 (GRCm39)	missense	probably damaging	1.00
R1927:Dicer1	UTSW	12	104,669,143 (GRCm39)	missense	possibly damaging	0.91
R2113:Dicer1	UTSW	12	104,679,473 (GRCm39)	missense	probably damaging	1.00
R2129:Dicer1	UTSW	12	104,688,290 (GRCm39)	missense	probably damaging	1.00
R2157:Dicer1	UTSW	12	104,669,208 (GRCm39)	missense	probably benign	0.17
R2202:Dicer1	UTSW	12	104,697,297 (GRCm39)	missense	possibly damaging	0.95
R2203:Dicer1	UTSW	12	104,697,297 (GRCm39)	missense	possibly damaging	0.95
R2243:Dicer1	UTSW	12	104,696,447 (GRCm39)	missense	probably damaging	0.99
R4237:Dicer1	UTSW	12	104,695,487 (GRCm39)	missense	possibly damaging	0.48
R4419:Dicer1	UTSW	12	104,671,373 (GRCm39)	missense	probably damaging	1.00
R4482:Dicer1	UTSW	12	104,672,536 (GRCm39)	missense	probably damaging	1.00
R4564:Dicer1	UTSW	12	104,671,010 (GRCm39)	nonsense	probably null
R4776:Dicer1	UTSW	12	104,658,705 (GRCm39)	missense	probably damaging	0.99
R4834:Dicer1	UTSW	12	104,662,850 (GRCm39)	missense	probably benign	0.44
R4904:Dicer1	UTSW	12	104,679,325 (GRCm39)	missense	probably benign
R5202:Dicer1	UTSW	12	104,660,990 (GRCm39)	nonsense	probably null
R5272:Dicer1	UTSW	12	104,670,499 (GRCm39)	missense	probably damaging	1.00
R5363:Dicer1	UTSW	12	104,669,410 (GRCm39)	missense	probably damaging	1.00
R5717:Dicer1	UTSW	12	104,671,387 (GRCm39)	missense	probably damaging	1.00
R6381:Dicer1	UTSW	12	104,662,721 (GRCm39)	missense	probably benign	0.00
R6479:Dicer1	UTSW	12	104,662,982 (GRCm39)	missense	probably damaging	0.97
R6956:Dicer1	UTSW	12	104,697,282 (GRCm39)	missense	probably damaging	1.00
R7234:Dicer1	UTSW	12	104,675,108 (GRCm39)	missense	probably damaging	1.00
R7401:Dicer1	UTSW	12	104,678,537 (GRCm39)	missense	probably benign
R7407:Dicer1	UTSW	12	104,688,610 (GRCm39)	nonsense	probably null
R7471:Dicer1	UTSW	12	104,660,969 (GRCm39)	missense	probably damaging	1.00
R7699:Dicer1	UTSW	12	104,671,429 (GRCm39)	missense	probably damaging	1.00
R7768:Dicer1	UTSW	12	104,672,956 (GRCm39)	missense	probably damaging	0.99
R7831:Dicer1	UTSW	12	104,675,059 (GRCm39)	missense	probably damaging	1.00
R7998:Dicer1	UTSW	12	104,670,328 (GRCm39)	missense	probably damaging	1.00
R8010:Dicer1	UTSW	12	104,658,391 (GRCm39)	missense	probably damaging	0.99
R8061:Dicer1	UTSW	12	104,669,077 (GRCm39)	nonsense	probably null
R8213:Dicer1	UTSW	12	104,668,952 (GRCm39)	missense	probably benign	0.00
R8261:Dicer1	UTSW	12	104,657,865 (GRCm39)	missense	probably damaging	1.00
R8419:Dicer1	UTSW	12	104,668,936 (GRCm39)	missense	probably benign	0.00
R8708:Dicer1	UTSW	12	104,694,704 (GRCm39)	missense	possibly damaging	0.65
R8851:Dicer1	UTSW	12	104,690,300 (GRCm39)	missense	possibly damaging	0.76
R9220:Dicer1	UTSW	12	104,679,415 (GRCm39)	missense	probably damaging	1.00
R9371:Dicer1	UTSW	12	104,670,991 (GRCm39)	missense	probably damaging	1.00
R9387:Dicer1	UTSW	12	104,695,499 (GRCm39)	missense	possibly damaging	0.48
R9505:Dicer1	UTSW	12	104,697,297 (GRCm39)	missense	possibly damaging	0.95
R9636:Dicer1	UTSW	12	104,688,406 (GRCm39)	nonsense	probably null
R9682:Dicer1	UTSW	12	104,672,484 (GRCm39)	missense	probably damaging	1.00
X0018:Dicer1	UTSW	12	104,663,193 (GRCm39)	missense	probably benign	0.00
Z1176:Dicer1	UTSW	12	104,697,279 (GRCm39)	missense	probably null	0.97

Protein Function and Prediction

Dicer1 encodes Dicer, a DEXH-box RNA helicase of the ribonuclease III family and functions in the generation of microRNAs (miRNAs) and small interfering RNAs (siRNAs), small noncoding RNAs that posttranscriptionally regulate genes (1-4). Dicer also interacts with TAR RNA-binding protein (TRBP) during RNA interference (2;5;6). The Dicer-TRBP complex binds to double-stranded RNA subsequently causing cleavage and the generation of siRNAs and miRNAs (2). One of the two strands of the siRNA/miRNA are than handed to the Argonaute (Ago) protein in the RNA-induced silencing complex (RISC). In the embryo, Dicer is essential for embryonic patterning and morphogenesis. In addition, Dicer functions in the proper morphogenesis of the vertebrate limb (4).

Expression/Localization

Dicer1 expression was detected in brain, heart, lung, liver, pancreas, kidney, and placenta, but not in skeletal muscle (1). Matsuda et al. suggest that Dicer1 is ubiquitously expressed, albeit at variable levels (1).

Background

Mutations in DICER1 are linked to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors [OMIM: #138800; (7)] and Pleuropulmonary blastoma [OMIM: #601200; (8)]. Multinodular goider is a common disorder characterized by nodular enlargement of the thyroid gland; some individuals may also develop Sertoli-Leydig cell tumors, usually of the ovary (7). Pleuropulmonary blastoma is a rare pediatric tumor of the lung that arises during fetal lung development and is often part of an inherited cancer syndrome (8).

Mice homozygous for a null allele survive until embryonic day (E) 7.5, before axis formation (9).

Dicer1^{tm1.1Bdh/tm1.1Bdh}; MGI:3589209

involves: 129

Homozygotes for this conditional null allele are embryonic lethal by E7.5 (4).

Dicer1^{tm1.1Snj/tm1.1Snj}; MGI:3809262

involves: 129S7/SvEvBrd * C57BL/6

Homozygotes for this null allele are embryonic lethal by E7.5 (10).

Dicer1^{tm1Ghan/tm1Ghan}; MGI:2681012

involves: 129S7/SvEvBrd

Homozygotes for this null allele are embryonic lethal by E7.5 (9).

Dicer1^tm1Gz/tm1Gz; MGI:3576927

involves: 129P2/OlaHsd * C57BL/6

Homozygotes are lethal between E12.5 and E14.5 and blood vessels are thin and poorly developed (11).

Dicer1^{Gt(RRF266)Byg/Gt(RRF266)Byg}; MGI:3719397

involves: 129P2/OlaHsd * C57BL/6

Homozygous animals exhibit partial perinatal lethality and have defects in angiogenesis (12;13). Mice also have decreased susceptibility to choriomemingitis virus, but higher susceptibility to vesicular stomatitis virus (VSV) or herpes simplex type 1 (HSV-1) (13).

Putative Mechanism

References

1. Matsuda, S., Ichigotani, Y., Okuda, T., Irimura, T., Nakatsugawa, S., and Hamaguchi, M. (2000) Molecular Cloning and Characterization of a Novel Human Gene (HERNA) which Encodes a Putative RNA-Helicase. Biochim Biophys Acta. 1490, 163-169.

2. Rossi, J. J. (2005) Mammalian Dicer Finds a Partner. EMBO Rep. 6, 927-929.

3. Filipowicz, W., Jaskiewicz, L., Kolb, F. A., and Pillai, R. S. (2005) Post-Transcriptional Gene Silencing by siRNAs and miRNAs. Curr Opin Struct Biol. 15, 331-341.

4. Harfe, B. D., McManus, M. T., Mansfield, J. H., Hornstein, E., and Tabin, C. J. (2005) The RNaseIII Enzyme Dicer is Required for Morphogenesis but Not Patterning of the Vertebrate Limb. Proc Natl Acad Sci U S A. 102, 10898-10903.

5. Haase, A. D., Jaskiewicz, L., Zhang, H., Laine, S., Sack, R., Gatignol, A., and Filipowicz, W. (2005) TRBP, a Regulator of Cellular PKR and HIV-1 Virus Expression, Interacts with Dicer and Functions in RNA Silencing. EMBO Rep. 6, 961-967.

6. Chendrimada, T. P., Gregory, R. I., Kumaraswamy, E., Norman, J., Cooch, N., Nishikura, K., and Shiekhattar, R. (2005) TRBP Recruits the Dicer Complex to Ago2 for microRNA Processing and Gene Silencing. Nature. 436, 740-744.

7. Rio Frio, T., Bahubeshi, A., Kanellopoulou, C., Hamel, N., Niedziela, M., Sabbaghian, N., Pouchet, C., Gilbert, L., O'Brien, P. K., Serfas, K., Broderick, P., Houlston, R. S., Lesueur, F., Bonora, E., Muljo, S., Schimke, R. N., Bouron-Dal Soglio, D., Arseneau, J., Schultz, K. A., Priest, J. R., Nguyen, V. H., Harach, H. R., Livingston, D. M., Foulkes, W. D., and Tischkowitz, M. (2011) DICER1 Mutations in Familial Multinodular Goiter with and without Ovarian Sertoli-Leydig Cell Tumors. JAMA. 305, 68-77.

8. Hill, D. A., Ivanovich, J., Priest, J. R., Gurnett, C. A., Dehner, L. P., Desruisseau, D., Jarzembowski, J. A., Wikenheiser-Brokamp, K. A., Suarez, B. K., Whelan, A. J., Williams, G., Bracamontes, D., Messinger, Y., and Goodfellow, P. J. (2009) DICER1 Mutations in Familial Pleuropulmonary Blastoma. Science. 325, 965.

9. Bernstein, E., Kim, S. Y., Carmell, M. A., Murchison, E. P., Alcorn, H., Li, M. Z., Mills, A. A., Elledge, S. J., Anderson, K. V., and Hannon, G. J. (2003) Dicer is Essential for Mouse Development. Nat Genet. 35, 215-217.

10. Mudhasani, R., Zhu, Z., Hutvagner, G., Eischen, C. M., Lyle, S., Hall, L. L., Lawrence, J. B., Imbalzano, A. N., and Jones, S. N. (2008) Loss of miRNA Biogenesis Induces p19Arf-p53 Signaling and Senescence in Primary Cells. J Cell Biol. 181, 1055-1063.

11. Yang, W. J., Yang, D. D., Na, S., Sandusky, G. E., Zhang, Q., and Zhao, G. (2005) Dicer is Required for Embryonic Angiogenesis during Mouse Development. J Biol Chem. 280, 9330-9335.

12. Otsuka, M., Jing, Q., Georgel, P., New, L., Chen, J., Mols, J., Kang, Y. J., Jiang, Z., Du, X., Cook, R., Das, S. C., Pattnaik, A. K., Beutler, B., and Han, J. (2007) Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice is due to Impaired miR24 and miR93 Expression. Immunity. 27, 123-134.

13. Fukasawa, M., Morita, S., Kimura, M., Horii, T., Ochiya, T., and Hatada, I. (2006) Genomic Imprinting in Dicer1-Hypomorphic Mice. Cytogenet Genome Res. 113, 138-143.

Posted On

2012-12-17

Science Writer

Anne Murray