Mutagenetix > Incidental Mutation

Incidental Mutation 'P0008:Dmpk'

7558

Institutional Source

Beutler Lab

Gene Symbol

Dmpk

Ensembl Gene

ENSMUSG00000030409

Gene Name

dystrophia myotonica-protein kinase

Synonyms

Dm15, DM

MMRRC Submission

038264-MU

Accession Numbers

Essential gene?

Possibly non essential (E-score: 0.421) question?

Stock #

P0008 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

18817774-18827746 bp(+) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

G to A at 18821987 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Arginine to Histidine at position 315 (R315H)

Ref Sequence

ENSEMBL: ENSMUSP00000118459 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000032568] [ENSMUST00000108473] [ENSMUST00000108474] [ENSMUST00000122999] [ENSMUST00000154199]

AlphaFold

P54265

Predicted Effect

possibly damaging
Transcript: ENSMUST00000032568
AA Change: R315H

PolyPhen 2 Score 0.820 (Sensitivity: 0.84; Specificity: 0.93)

SMART Domains

Protein: ENSMUSP00000032568
Gene: ENSMUSG00000030409
AA Change: R315H

Domain	Start	End	E-Value	Type
low complexity region	5	31	N/A	INTRINSIC
S_TKc	71	339	6.5e-87	SMART
S_TK_X	340	407	3.6e-11	SMART
Pfam:DMPK_coil	472	532	2.8e-25	PFAM
low complexity region	590	613	N/A	INTRINSIC

Predicted Effect

possibly damaging
Transcript: ENSMUST00000108473
AA Change: R315H

PolyPhen 2 Score 0.820 (Sensitivity: 0.84; Specificity: 0.93)

SMART Domains

Protein: ENSMUSP00000104113
Gene: ENSMUSG00000030409
AA Change: R315H

Domain	Start	End	E-Value	Type
low complexity region	5	31	N/A	INTRINSIC
S_TKc	71	339	1.36e-84	SMART
S_TK_X	340	407	7.5e-9	SMART
Pfam:DMPK_coil	472	532	2.2e-28	PFAM

Predicted Effect

possibly damaging
Transcript: ENSMUST00000108474
AA Change: R315H

PolyPhen 2 Score 0.886 (Sensitivity: 0.82; Specificity: 0.94)

SMART Domains

Protein: ENSMUSP00000104114
Gene: ENSMUSG00000030409
AA Change: R315H

Domain	Start	End	E-Value	Type
low complexity region	5	31	N/A	INTRINSIC
S_TKc	71	336	2.57e-76	SMART
Pfam:DMPK_coil	446	506	2.4e-28	PFAM
low complexity region	564	587	N/A	INTRINSIC

Predicted Effect

probably benign
Transcript: ENSMUST00000122999

SMART Domains

Protein: ENSMUSP00000123516
Gene: ENSMUSG00000030409

Domain	Start	End	E-Value	Type
low complexity region	5	31	N/A	INTRINSIC
PDB:2VD5\|B	32	139	3e-62	PDB
SCOP:d1koba_	44	139	3e-21	SMART
Blast:S_TKc	71	139	7e-36	BLAST

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000126264

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000128422

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000132115

Predicted Effect

possibly damaging
Transcript: ENSMUST00000154199
AA Change: R315H

PolyPhen 2 Score 0.894 (Sensitivity: 0.82; Specificity: 0.94)

SMART Domains

Protein: ENSMUSP00000118459
Gene: ENSMUSG00000030409
AA Change: R315H

Domain	Start	End	E-Value	Type
low complexity region	5	31	N/A	INTRINSIC
S_TKc	71	339	1.36e-84	SMART
S_TK_X	340	402	5.3e-9	SMART
Pfam:DMPK_coil	467	527	2.3e-28	PFAM

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000135839

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000149188

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000148380

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000140742

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000143938

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000137219

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000148472

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000147215

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000152050

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000174918

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000142725

Meta Mutation Damage Score

0.1795

Coding Region Coverage

1x: 86.8%
3x: 83.1%
10x: 72.7%
20x: 59.5%

Validation Efficiency

70% (420/599)

MGI Phenotype

FUNCTION: The protein encoded by this gene is a serine/threonine protein kinase that contains coiled-coil and C-terminal membrane association domains. In the embryonic mouse, it is found in cardiac and skeletal myocytes where it appears to play a role in myogenesis. In adults, the transcript is localized to several tissues including brain, heart, and skeletal and smooth muscle, and a function in cytoskeletal remodeling has been described. Transcripts with expanded CUG repeats in the 3' untranslated region mediate alternative splicing of several genes and sequester RNA binding proteins and RNA transcripts that contain CAG repeats, resulting in myotonic dystrophy, an autosomal dominant neuromuscular disorder. Alternative splicing results in multiple protein coding and non-coding transcript variants. [provided by RefSeq, Oct 2014]
PHENOTYPE: Homozygotes for a null mutation exhibit abnormal sodium channel gating in cardiac myocytes, cardiac conduction defects, and late-onset progressive skeletal myopathy. Homozygotes for a second null mutation do not develop skeletal myopathy but do have abnormal muscle intracellular calcium levels. [provided by MGI curators]

Allele List at MGI

All alleles(4) : Targeted(4)

Other mutations in this stock

Total: 9 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Agpat3	T	C	10: 78,123,710 (GRCm39)	N50S	probably damaging	Het
Cfap70	A	T	14: 20,466,600 (GRCm39)	F550I	probably damaging	Het
Dnah5	T	A	15: 28,302,533 (GRCm39)	Y1597N	probably damaging	Het
Mocos	A	T	18: 24,812,663 (GRCm39)	Q519L	probably benign	Het
Mycbpap	T	A	11: 94,394,893 (GRCm39)	D270V	probably damaging	Het
Pkp1	T	C	1: 135,803,421 (GRCm39)	M712V	probably benign	Het
Sgtb	T	C	13: 104,260,782 (GRCm39)	V77A	probably damaging	Het
Srpk2	T	C	5: 23,718,976 (GRCm39)	Y613C	probably damaging	Het
Wwc1	T	C	11: 35,744,178 (GRCm39)		probably benign	Het

Other mutations in Dmpk

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL02198:Dmpk	APN	7	18,822,117 (GRCm39)	missense	probably damaging	0.98
IGL02874:Dmpk	APN	7	18,820,926 (GRCm39)	missense	possibly damaging	0.75
IGL02942:Dmpk	APN	7	18,826,166 (GRCm39)	missense	probably damaging	0.99
IGL03081:Dmpk	APN	7	18,821,458 (GRCm39)	missense	probably damaging	1.00
IGL03258:Dmpk	APN	7	18,826,131 (GRCm39)	critical splice acceptor site	probably null
IGL03302:Dmpk	APN	7	18,820,411 (GRCm39)	splice site	probably benign
R0388:Dmpk	UTSW	7	18,818,002 (GRCm39)	unclassified	probably benign
R0961:Dmpk	UTSW	7	18,821,195 (GRCm39)	missense	probably damaging	0.99
R3103:Dmpk	UTSW	7	18,821,579 (GRCm39)	missense	probably damaging	1.00
R3157:Dmpk	UTSW	7	18,826,944 (GRCm39)	missense	probably benign	0.00
R3158:Dmpk	UTSW	7	18,826,944 (GRCm39)	missense	probably benign	0.00
R3159:Dmpk	UTSW	7	18,826,944 (GRCm39)	missense	probably benign	0.00
R3498:Dmpk	UTSW	7	18,820,306 (GRCm39)	missense	probably damaging	1.00
R4696:Dmpk	UTSW	7	18,822,139 (GRCm39)	missense	probably damaging	1.00
R4830:Dmpk	UTSW	7	18,821,453 (GRCm39)	missense	probably damaging	1.00
R4991:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5156:Dmpk	UTSW	7	18,818,050 (GRCm39)	missense	probably damaging	1.00
R5169:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5170:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5171:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5172:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5198:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5200:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5202:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5205:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5383:Dmpk	UTSW	7	18,821,944 (GRCm39)	missense	probably benign	0.05
R5449:Dmpk	UTSW	7	18,824,916 (GRCm39)	missense	probably benign	0.18
R5639:Dmpk	UTSW	7	18,826,525 (GRCm39)	missense	probably benign	0.22
R5874:Dmpk	UTSW	7	18,826,007 (GRCm39)	intron	probably benign
R6939:Dmpk	UTSW	7	18,822,149 (GRCm39)	missense	probably damaging	0.97
R7133:Dmpk	UTSW	7	18,821,232 (GRCm39)	missense	probably damaging	1.00
R7352:Dmpk	UTSW	7	18,819,997 (GRCm39)	missense	probably damaging	0.98
R8032:Dmpk	UTSW	7	18,821,978 (GRCm39)	missense	possibly damaging	0.63
R8234:Dmpk	UTSW	7	18,822,048 (GRCm39)	missense	probably benign	0.00
R8886:Dmpk	UTSW	7	18,825,886 (GRCm39)	unclassified	probably benign
R9052:Dmpk	UTSW	7	18,821,614 (GRCm39)	missense	probably damaging	0.99
R9235:Dmpk	UTSW	7	18,822,141 (GRCm39)	missense	probably damaging	1.00
R9420:Dmpk	UTSW	7	18,824,946 (GRCm39)	missense	probably benign	0.01

Protein Function and Prediction

DMPK is considered to be a member of the subfamily of Rho-kinases (1). This family of proteins are proposed to function in cell shape determination and in the regulation of actin-myosin contractility (1).

Expression/Localization

DMPK transcripts and proteins can be found in several tissues, with the highest expression in organs containing smooth muscle cell linings (stomach and colon) and in cardiac and skeletal muscles (most prominent in tongue, esophagus and diaphragm) (2;3). Dmpk is localized predominantly to neuromuscular and myotendinous junctions in skeletal muscles from both human and mouse (4).

Background

Dystrophia myotonica protein kinase (Dmpk) is expressed at lower levels in skeletal and cardiac muscle extracts from patients with myotonic dystrophy 1 (OMIM: #160900) (4) a condition characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. Further studies determined that myotonic dystrophy is caused by (CTG)n-repeat expansion in Dmpk (5). Findings from a Dmpk knockout mouse model (MGI:3054407) indicate that Dmpk modulates excitation-contraction coupling in skeletal muscle.

Dmpk^{tm1Bew/tm1Bew}; MGI:3054407

involves: 129P2/OlaHsd * C57BL/6

In this model, basal intracellular calcium is increased and calcium depolarization response provoked by acetylcholine or KCl are reduced in cultured skeletal muscles from homozygous mutants (6); mutants do not show any of the expected signs of myotonic dystrophy (2)

Dmpk^{tm1Rdd/tm1Rdd} ; MGI:2182402

involves: 129S2/SvPas * C57BL/6J

These mice develop develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM (OMIM: #160900) (7). Muscles from this model have loss of sarcomeric organization and focal loss of Z lines as well as dilation of the sarcoplasmic reticulum. By 7-11 months, sternomastoic muscles have variable fiber size and a 30-50% recuction in twitch and tetanic force generation (7). Homozygotes also exhibit a progressive increase in skeletal muscle regenerative activity, progressive muscle weakness, and myopathy (7).

Additional studies with this model found that mutant ventricular homogenates exhibit significantly reduced Ca²⁺ uptake in cardiomyocyte sarcoplasmic reticulum (SR) (8). Also, adult homozygotes display distinct atrioventricular conduction abnormalities in the presence of normal intrinsic sinus node function (9).

References

1. Groenen, P. J., Wansink, D. G., Coerwinkel, M., van den Broek, W., Jansen, G., and Wieringa, B. (2000) Constitutive and Regulated Modes of Splicing Produce Six Major Myotonic Dystrophy Protein Kinase (DMPK) Isoforms with Distinct Properties. Hum Mol Genet. 9, 605-616.

2. Jansen, G., Groenen, P. J., Bachner, D., Jap, P. H., Coerwinkel, M., Oerlemans, F., van den Broek, W., Gohlsch, B., Pette, D., Plomp, J. J., Molenaar, P. C., Nederhoff, M. G., van Echteld, C. J., Dekker, M., Berns, A., Hameister, H., and Wieringa, B. (1996) Abnormal Myotonic Dystrophy Protein Kinase Levels Produce Only Mild Myopathy in Mice. Nat Genet. 13, 316-324.

3. Balasubramanyam, A., Iyer, D., Stringer, J. L., Beaulieu, C., Potvin, A., Neumeyer, A. M., Avruch, J., and Epstein, H. F. (1998) Developmental Changes in Expression of Myotonic Dystrophy Protein Kinase in the Rat Central Nervous System. J Comp Neurol. 394, 309-325.

4. van der Ven, P. F., Jansen, G., van Kuppevelt, T. H., Perryman, M. B., Lupa, M., Dunne, P. W., ter Laak, H. J., Jap, P. H., Veerkamp, J. H., and Epstein, H. F. (1993) Myotonic Dystrophy Kinase is a Component of Neuromuscular Junctions. Hum Mol Genet. 2, 1889-1894.

5. Brook, J. D., McCurrach, M. E., Harley, H. G., Buckler, A. J., Church, D., Aburatani, H., Hunter, K., Stanton, V. P., Thirion, J. P., and Hudson, T. (1992) Molecular Basis of Myotonic Dystrophy: Expansion of a Trinucleotide (CTG) Repeat at the 3' End of a Transcript Encoding a Protein Kinase Family Member. Cell. 68, 799-808.

6. Benders, A. A., Groenen, P. J., Oerlemans, F. T., Veerkamp, J. H., and Wieringa, B. (1997) Myotonic Dystrophy Protein Kinase is Involved in the Modulation of the Ca2+ Homeostasis in Skeletal Muscle Cells. J Clin Invest. 100, 1440-1447.

7. Reddy, S., Smith, D. B., Rich, M. M., Leferovich, J. M., Reilly, P., Davis, B. M., Tran, K., Rayburn, H., Bronson, R., Cros, D., Balice-Gordon, R. J., and Housman, D. (1996) Mice Lacking the Myotonic Dystrophy Protein Kinase Develop a Late Onset Progressive Myopathy. Nat Genet. 13, 325-335.

8. Kaliman, P., Catalucci, D., Lam, J. T., Kondo, R., Gutierrez, J. C., Reddy, S., Palacin, M., Zorzano, A., Chien, K. R., and Ruiz-Lozano, P. (2005) Myotonic Dystrophy Protein Kinase Phosphorylates Phospholamban and Regulates Calcium Uptake in Cardiomyocyte Sarcoplasmic Reticulum. J Biol Chem. 280, 8016-8021.

9. Berul, C. I., Maguire, C. T., Aronovitz, M. J., Greenwood, J., Miller, C., Gehrmann, J., Housman, D., Mendelsohn, M. E., and Reddy, S. (1999) DMPK Dosage Alterations Result in Atrioventricular Conduction Abnormalities in a Mouse Myotonic Dystrophy Model. J Clin Invest. 103, R1-7.

Posted On

2012-10-04

Science Writer

Anne Murray