Mutagenetix > Incidental Mutation

Incidental Mutation 'P0016:Rnaseh2a'

7604

Institutional Source

Beutler Lab

Gene Symbol

Rnaseh2a

Ensembl Gene

ENSMUSG00000052926

Gene Name

ribonuclease H2, large subunit

Synonyms

2400006P09Rik

MMRRC Submission

038269-MU

Accession Numbers

Essential gene?

Probably essential (E-score: 0.968) question?

Stock #

P0016 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

85683239-85694498 bp(-) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

C to G at 85686429 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Aspartic acid to Histidine at position 206 (D206H)

Ref Sequence

ENSEMBL: ENSMUSP00000120374 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000065049] [ENSMUST00000067472] [ENSMUST00000109736] [ENSMUST00000109738] [ENSMUST00000109740] [ENSMUST00000121880] [ENSMUST00000128972] [ENSMUST00000147812] [ENSMUST00000152378]

AlphaFold

Q9CWY8

Predicted Effect

possibly damaging
Transcript: ENSMUST00000065049
AA Change: D206H

PolyPhen 2 Score 0.787 (Sensitivity: 0.85; Specificity: 0.93)

SMART Domains

Protein: ENSMUSP00000066769
Gene: ENSMUSG00000052926
AA Change: D206H

Domain	Start	End	E-Value	Type
Pfam:RNase_HII	31	242	7.1e-54	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000067472

SMART Domains

Protein: ENSMUSP00000070558
Gene: ENSMUSG00000048617

Domain	Start	End	E-Value	Type
Pfam:Folate_rec	27	203	2e-40	PFAM
low complexity region	224	234	N/A	INTRINSIC

Predicted Effect

probably damaging
Transcript: ENSMUST00000109736
AA Change: D206H

PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)

SMART Domains

Protein: ENSMUSP00000105358
Gene: ENSMUSG00000052926
AA Change: D206H

Domain	Start	End	E-Value	Type
Pfam:RNase_HII	31	242	1.3e-51	PFAM

Predicted Effect

probably damaging
Transcript: ENSMUST00000109738
AA Change: D206H

PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)

SMART Domains

Protein: ENSMUSP00000105360
Gene: ENSMUSG00000052926
AA Change: D206H

Domain	Start	End	E-Value	Type
Pfam:RNase_HII	31	242	5.5e-53	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000109740

SMART Domains

Protein: ENSMUSP00000105362
Gene: ENSMUSG00000048617

Domain	Start	End	E-Value	Type
Pfam:Folate_rec	27	203	3.5e-42	PFAM
low complexity region	224	234	N/A	INTRINSIC

Predicted Effect

probably benign
Transcript: ENSMUST00000121880

SMART Domains

Protein: ENSMUSP00000113982
Gene: ENSMUSG00000048617

Domain	Start	End	E-Value	Type
Pfam:Folate_rec	27	203	3.5e-42	PFAM
low complexity region	224	234	N/A	INTRINSIC

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000122931

Predicted Effect

possibly damaging
Transcript: ENSMUST00000128972
AA Change: D206H

PolyPhen 2 Score 0.587 (Sensitivity: 0.87; Specificity: 0.91)

SMART Domains

Protein: ENSMUSP00000121864
Gene: ENSMUSG00000052926
AA Change: D206H

Domain	Start	End	E-Value	Type
signal peptide	1	22	N/A	INTRINSIC
Pfam:RNase_HII	57	268	1.4e-53	PFAM

Predicted Effect

probably damaging
Transcript: ENSMUST00000147812
AA Change: D206H

PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)

SMART Domains

Protein: ENSMUSP00000120374
Gene: ENSMUSG00000052926
AA Change: D206H

Domain	Start	End	E-Value	Type
Pfam:RNase_HII	31	242	1.3e-51	PFAM

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000126029

Predicted Effect

probably benign
Transcript: ENSMUST00000152378

SMART Domains

Protein: ENSMUSP00000132841
Gene: ENSMUSG00000048617

Domain	Start	End	E-Value	Type
Pfam:Folate_rec	2	172	2.8e-38	PFAM
low complexity region	193	203	N/A	INTRINSIC

Meta Mutation Damage Score

0.2077

Coding Region Coverage

1x: 85.6%
3x: 81.0%
10x: 66.8%
20x: 50.1%

Validation Efficiency

96% (97/101)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNAseH2). RNAseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes. Mutations in this gene cause Aicardi-Goutieres Syndrome (AGS), a an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid.[provided by RefSeq, Aug 2009]

Allele List at MGI

All alleles(33) : Targeted(1) Gene trapped(32)

Other mutations in this stock

Total: 18 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
1700123K08Rik	A	T	5: 138,561,200 (GRCm39)	L154*	probably null	Het
4930432E11Rik	T	C	7: 29,262,537 (GRCm39)		noncoding transcript	Het
Arap3	T	A	18: 38,117,401 (GRCm39)	T892S	probably benign	Het
Ctnnd2	G	A	15: 30,967,084 (GRCm39)	V987I	probably benign	Het
Dennd6b	T	C	15: 89,071,180 (GRCm39)	I351V	probably benign	Het
Kif27	G	A	13: 58,451,266 (GRCm39)	Q1021*	probably null	Het
Klb	G	A	5: 65,537,266 (GRCm39)	W865*	probably null	Het
Mbd1	C	T	18: 74,407,609 (GRCm39)	R130*	probably null	Het
Mroh7	T	A	4: 106,565,054 (GRCm39)		probably null	Het
Myo16	C	T	8: 10,450,596 (GRCm39)		probably benign	Het
Rbm22	T	A	18: 60,703,842 (GRCm39)		probably benign	Het
Slain1	A	G	14: 103,923,110 (GRCm39)	T187A	probably benign	Het
Slamf6	A	G	1: 171,764,068 (GRCm39)	T154A	probably damaging	Het
Traip	A	G	9: 107,845,855 (GRCm39)	D316G	possibly damaging	Het
Ttn	T	C	2: 76,641,527 (GRCm39)	D5196G	probably damaging	Het
Ubr5	C	T	15: 38,000,822 (GRCm39)	V1569M	probably damaging	Het
Zfp750	T	A	11: 121,404,804 (GRCm39)	K24*	probably null	Het
Zfp799	T	C	17: 33,038,331 (GRCm39)	E645G	possibly damaging	Het

Other mutations in Rnaseh2a

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL01318:Rnaseh2a	APN	8	85,691,752 (GRCm39)	unclassified	probably benign
IGL01773:Rnaseh2a	APN	8	85,691,767 (GRCm39)	missense	probably damaging	1.00
IGL02606:Rnaseh2a	APN	8	85,686,723 (GRCm39)	missense	probably damaging	1.00
R1521:Rnaseh2a	UTSW	8	85,692,487 (GRCm39)	critical splice donor site	probably null
R2270:Rnaseh2a	UTSW	8	85,692,048 (GRCm39)	missense	probably benign	0.03
R4226:Rnaseh2a	UTSW	8	85,686,702 (GRCm39)	missense	possibly damaging	0.72
R4227:Rnaseh2a	UTSW	8	85,686,702 (GRCm39)	missense	possibly damaging	0.72
R4763:Rnaseh2a	UTSW	8	85,692,021 (GRCm39)	missense	probably benign	0.02
R5344:Rnaseh2a	UTSW	8	85,684,735 (GRCm39)	unclassified	probably benign
R8000:Rnaseh2a	UTSW	8	85,692,678 (GRCm39)	unclassified	probably benign
R8354:Rnaseh2a	UTSW	8	85,691,776 (GRCm39)	missense	probably benign
R8454:Rnaseh2a	UTSW	8	85,691,776 (GRCm39)	missense	probably benign
R8964:Rnaseh2a	UTSW	8	85,686,434 (GRCm39)	missense	probably benign	0.00
R9710:Rnaseh2a	UTSW	8	85,684,638 (GRCm39)	missense	probably damaging	1.00
R9735:Rnaseh2a	UTSW	8	85,686,661 (GRCm39)	missense	probably damaging	1.00
RF008:Rnaseh2a	UTSW	8	85,686,687 (GRCm39)	nonsense	probably null

Protein Function and Prediction

RNase H2 is an enzyme that hydrolyzes the RNA strand from RNA/DNA hybrids during DNA replication, transcription, and telomere elongation (1). RNase H2 also can cleave the 5′-phosphodiester bond of one or more ribonucleotides embedded in a DNA duplex (2). RNaseH2a is one of three subunits within the eukaryotic RNase H2 complex (3).

Background

Mutations in RNASEH2A are linked to Aicardi-Goutieres syndrome (OMIM # 610333), an autosomal recessive encephalopathy characterized in its most severe form by cerebral atrophy, leukodystrophy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infections (4). AGS is phenotypically similar to congenital viral brain infection (5). Severe neurologic dysfunction becomes clinically apparent in infancy, and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood. Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated hepatic transaminases along with intermittent fever may also erroneously suggest an infective process (6).

References

1. Reijns, M. A., Bubeck, D., Gibson, L. C., Graham, S. C., Baillie, G. S., Jones, E. Y., and Jackson, A. P. (2011) The Structure of the Human RNase H2 Complex Defines Key Interaction Interfaces Relevant to Enzyme Function and Human Disease. J Biol Chem. 286, 10530-10539.

2. Eder, P. S., and Walder, J. A. (1991) Ribonuclease H from K562 Human Erythroleukemia Cells. Purification, Characterization, and Substrate Specificity. J Biol Chem. 266, 6472-6479.

3. Jeong, H. S., Backlund, P. S., Chen, H. C., Karavanov, A. A., and Crouch, R. J. (2004) RNase H2 of Saccharomyces Cerevisiae is a Complex of Three Proteins. Nucleic Acids Res. 32, 407-414.

4. Ali, M., Highet, L. J., Lacombe, D., Goizet, C., King, M. D., Tacke, U., van der Knaap, M. S., Lagae, L., Rittey, C., Brunner, H. G., van Bokhoven, H., Hamel, B., Oade, Y. A., Sanchis, A., Desguerre, I., Cau, D., Mathieu, N., Moutard, M. L., Lebon, P., Kumar, D., Jackson, A. P., and Crow, Y. J. (2006) A Second Locus for Aicardi-Goutieres Syndrome at Chromosome 13q14-21. J Med Genet. 43, 444-450.

5. Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., Bertini, E., Chandler, K. E., Chitayat, D., Cau, D., Dery, C., Fazzi, E., Goizet, C., King, M. D., Klepper, J., Lacombe, D., Lanzi, G., Lyall, H., Martinez-Frias, M. L., Mathieu, M., McKeown, C., Monier, A., Oade, Y., Quarrell, O. W., Rittey, C. D., Rogers, R. C., Sanchis, A., Stephenson, J. B., Tacke, U., Till, M., Tolmie, J. L., Tomlin, P., Voit, T., Weschke, B., Woods, C. G., Lebon, P., Bonthron, D. T., Ponting, C. P., and Jackson, A. P. (2006) Mutations in Genes Encoding Ribonuclease H2 Subunits Cause Aicardi-Goutieres Syndrome and Mimic Congenital Viral Brain Infection. Nat Genet. 38, 910-916.

6. Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., Frints, S. G., Klepper, J., Livingston, J. H., Lynch, S. A., Massey, R. F., Meritet, J. F., Michaud, J. L., Ponsot, G., Voit, T., Lebon, P., Bonthron, D. T., Jackson, A. P., Barnes, D. E., and Lindahl, T. (2006) Mutations in the Gene Encoding the 3'-5' DNA Exonuclease TREX1 Cause Aicardi-Goutieres Syndrome at the AGS1 Locus. Nat Genet. 38, 917-920.

Posted On

2012-10-05

Science Writer

Anne Murray