Mutagenetix > Incidental Mutation

Incidental Mutation 'R0006:Tpm3'

8184

Institutional Source

Beutler Lab

Gene Symbol

Tpm3

Ensembl Gene

ENSMUSG00000027940

Gene Name

tropomyosin 3, gamma

Synonyms

hTM30nm, Tpm-5, skalphaTM.2, Trop-5, gamma-TM, hTMnm, Tm5NM, Tpm5

MMRRC Submission

041980-MU

Accession Numbers

Essential gene?

Essential (E-score: 1.000) question?

Stock #

R0006 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

89979958-90008209 bp(+) (GRCm39)

Type of Mutation

splice site

DNA Base Change (assembly)

T to A at 89994968 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Ref Sequence

ENSEMBL: ENSMUSP00000114229 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000029549] [ENSMUST00000118566] [ENSMUST00000119158] [ENSMUST00000119570] [ENSMUST00000121503] [ENSMUST00000127955] [ENSMUST00000149432]

AlphaFold

no structure available at present

Predicted Effect

probably benign
Transcript: ENSMUST00000029549

SMART Domains

Protein: ENSMUSP00000029549
Gene: ENSMUSG00000027940

Domain	Start	End	E-Value	Type
Pfam:Tropomyosin_1	4	117	3.9e-22	PFAM
Pfam:Tropomyosin	12	248	7.2e-93	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000118566

SMART Domains

Protein: ENSMUSP00000113056
Gene: ENSMUSG00000027940

Domain	Start	End	E-Value	Type
Pfam:Tropomyosin_1	3	117	2e-21	PFAM
Pfam:Tropomyosin	12	248	1.7e-100	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000119158

SMART Domains

Protein: ENSMUSP00000113219
Gene: ENSMUSG00000027940

Domain	Start	End	E-Value	Type
Pfam:Tropomyosin_1	4	117	1.7e-22	PFAM
Pfam:Tropomyosin	12	247	3.9e-96	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000119570

SMART Domains

Protein: ENSMUSP00000113978
Gene: ENSMUSG00000027940

Domain	Start	End	E-Value	Type
Pfam:Tropomyosin_1	8	154	4.2e-35	PFAM
Pfam:CLZ	10	75	1.2e-9	PFAM
Pfam:Tropomyosin	49	285	3.7e-91	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000121503

SMART Domains

Protein: ENSMUSP00000113578
Gene: ENSMUSG00000027940

Domain	Start	End	E-Value	Type
Pfam:Tropomyosin_1	7	153	1.3e-36	PFAM
Pfam:Tropomyosin	48	284	4.7e-103	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000127955

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000131354

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000151798

Predicted Effect

probably benign
Transcript: ENSMUST00000149432

SMART Domains

Protein: ENSMUSP00000114229
Gene: ENSMUSG00000027940

Domain	Start	End	E-Value	Type
Pfam:Tropomyosin	1	70	1.6e-28	PFAM

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000133281

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000133361

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000147430

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000149115

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000136125

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000149734

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000143281

Coding Region Coverage

1x: 77.9%
3x: 66.3%
10x: 36.9%
20x: 17.4%

Validation Efficiency

95% (74/78)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the tropomyosin family of actin-binding proteins. Tropomyosins are dimers of coiled-coil proteins that provide stability to actin filaments and regulate access of other actin-binding proteins. Mutations in this gene result in autosomal dominant nemaline myopathy and other muscle disorders. This locus is involved in translocations with other loci, including anaplastic lymphoma receptor tyrosine kinase (ALK) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), which result in the formation of fusion proteins that act as oncogenes. There are numerous pseudogenes for this gene on different chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]
PHENOTYPE: Homozygous inactivation of this gene results in early embryonic death, prior to blastocyst formation. Mice homozygous for a targeted allele lacking exon 9 exhibit dysmorphic T-tubules and contraction in skeletal muscles. [provided by MGI curators]

Allele List at MGI

All alleles(76) : Targeted(5) Gene trapped(71)

Other mutations in this stock

Total: 26 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Appl2	A	G	10: 83,438,762 (GRCm39)	F556L	probably damaging	Het
Atad2b	T	A	12: 4,992,030 (GRCm39)	S210T	possibly damaging	Het
Aurka	A	G	2: 172,201,673 (GRCm39)		probably null	Het
Chd8	A	G	14: 52,472,750 (GRCm39)	I351T	possibly damaging	Het
Chid1	T	A	7: 141,076,339 (GRCm39)		probably benign	Het
Dnase2b	T	A	3: 146,288,244 (GRCm39)	I284F	probably damaging	Het
Dst	C	T	1: 34,267,999 (GRCm39)	T5325I	probably benign	Het
Erbb3	A	G	10: 128,409,279 (GRCm39)		probably null	Het
Fancl	A	G	11: 26,419,695 (GRCm39)	N316S	possibly damaging	Het
Gabrd	C	A	4: 155,473,058 (GRCm39)	V72L	probably damaging	Het
Hephl1	T	A	9: 14,988,060 (GRCm39)	T683S	probably benign	Het
Jazf1	A	G	6: 52,871,071 (GRCm39)		probably benign	Het
Kntc1	T	A	5: 123,927,201 (GRCm39)	S1219T	probably benign	Het
L3mbtl1	A	T	2: 162,806,489 (GRCm39)	Y460F	possibly damaging	Het
Map1b	C	T	13: 99,571,810 (GRCm39)	V304M	probably damaging	Het
Msantd4	A	G	9: 4,384,099 (GRCm39)	E140G	probably damaging	Het
Myo16	A	G	8: 10,525,988 (GRCm39)	K843E	probably damaging	Het
Rap1gds1	G	T	3: 138,689,632 (GRCm39)		probably null	Het
Rsph4a	T	C	10: 33,785,144 (GRCm39)	C148R	probably damaging	Het
Slc7a9	A	T	7: 35,169,525 (GRCm39)		probably benign	Het
Sptbn1	A	G	11: 30,073,855 (GRCm39)	S1405P	probably damaging	Het
Tex35	T	C	1: 156,927,314 (GRCm39)	K154E	possibly damaging	Het
Ubr4	T	C	4: 139,158,960 (GRCm39)	F2438L	probably benign	Het
Wfdc8	T	C	2: 164,440,984 (GRCm39)	D253G	probably damaging	Het
Zfp451	A	T	1: 33,841,861 (GRCm39)		probably benign	Het
Zfp687	A	G	3: 94,918,767 (GRCm39)	I335T	probably damaging	Het

Other mutations in Tpm3

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL00481:Tpm3	APN	3	89,995,024 (GRCm39)	missense	probably damaging	0.99
IGL00949:Tpm3	APN	3	89,997,165 (GRCm39)	missense	probably damaging	1.00
IGL01955:Tpm3	APN	3	89,995,742 (GRCm39)	missense	probably benign	0.00
IGL01970:Tpm3	APN	3	89,997,135 (GRCm39)	missense	probably damaging	1.00
IGL02605:Tpm3	APN	3	89,995,753 (GRCm39)	missense	probably benign	0.13
IGL03352:Tpm3	APN	3	89,995,052 (GRCm39)	critical splice donor site	probably null
IGL03375:Tpm3	APN	3	89,981,079 (GRCm39)	missense	possibly damaging	0.83
P0045:Tpm3	UTSW	3	89,998,400 (GRCm39)	critical splice donor site	probably null
R0006:Tpm3	UTSW	3	89,994,968 (GRCm39)	splice site	probably benign
R0024:Tpm3	UTSW	3	89,994,756 (GRCm39)	splice site	probably null
R0086:Tpm3	UTSW	3	89,997,399 (GRCm39)	unclassified	probably benign
R1487:Tpm3	UTSW	3	89,997,389 (GRCm39)	splice site	probably null
R5235:Tpm3	UTSW	3	89,993,802 (GRCm39)	missense	probably damaging	1.00
R6639:Tpm3	UTSW	3	89,987,109 (GRCm39)	missense	probably damaging	0.99
R7089:Tpm3	UTSW	3	89,980,029 (GRCm39)	start gained	probably benign
R7212:Tpm3	UTSW	3	89,998,361 (GRCm39)	missense	probably benign
R7867:Tpm3	UTSW	3	89,993,775 (GRCm39)	missense	probably damaging	1.00
R8322:Tpm3	UTSW	3	89,981,011 (GRCm39)	intron	probably benign
R8701:Tpm3	UTSW	3	89,994,987 (GRCm39)	missense	possibly damaging	0.68
R9167:Tpm3	UTSW	3	89,994,824 (GRCm39)	missense	probably benign	0.13
X0020:Tpm3	UTSW	3	89,994,881 (GRCm39)	critical splice donor site	probably null

Protein Function and Prediction

Tropomyosins are components of the thin filaments of the sarcomere; TPM3 is expressed predominantly in slow, type 1 muscle fibers (1). They function to mediate the effect of calcium on the actin-myosin interaction (1). TPM3, along with TPM1 encode the alpha subunit of the muscle tropomyosin alpha-beta dimer; TPM2 encodes the beta subunit [reviewed in (2)]. A knockout mouse model determined that TPM3 is required for embryonic development and cell survival (3).

Background

Phenotype	OMIM #	Brief Description	Refs
CAP myopathy	609284	Congenital muscular dystrophy associated with cap structures on skeletal muscle biopsy; patients have slowly progressive muscle weakness and/or delayed motor development	(4;5)
Myopathy, congenital, with fiber-type disproportion	255310	Disorder in which there is relative hypotrophy of type 1 muscle fibers; patients often have muscle weakness and failure to thrive	(6)
Nemaline myopathy 1, autosomal dominant	609284	A form of congenital myopathy characterized by abnormal thread- or rod-like structures in muscle fibers on histologic examination; the clinical phenotype is highly variable, with differing age at onset and severity	(1;7;8)

An autosomal dominant mouse mimicked patients with nemaline myopathy in that they exhibited muscle weakness at 5-6 months of age as well as rods present in all muscles and hypertrophy of fast, glycolytic fibres (9).

Tpm3^{tm1Pgun/tm1Pgun}; MGI:3040795

involves: 129X1/SvJ

Homozygous inactivation of this gene results in early embryonic death, prior to blastocyst formation (3).

References

1. Laing, N. G., Wilton, S. D., Akkari, P. A., Dorosz, S., Boundy, K., Kneebone, C., Blumbergs, P., White, S., Watkins, H., and Love, D. R. (1995) A Mutation in the Alpha Tropomyosin Gene TPM3 Associated with Autosomal Dominant Nemaline Myopathy NEM1. Nat Genet. 10, 249.

2. Clarkson, E., Costa, C. F., and Machesky, L. M. (2004) Congenital Myopathies: Diseases of the Actin Cytoskeleton. J Pathol. 204, 407-417.

3. Hook, J., Lemckert, F., Qin, H., Schevzov, G., and Gunning, P. (2004) Gamma Tropomyosin Gene Products are Required for Embryonic Development. Mol Cell Biol. 24, 2318-2323.

4. De Paula, A. M., Franques, J., Fernandez, C., Monnier, N., Lunardi, J., Pellissier, J. F., Figarella-Branger, D., and Pouget, J. (2009) A TPM3 Mutation Causing Cap Myopathy. Neuromuscul Disord. 19, 685-688.

5. Ohlsson, M., Fidzianska, A., Tajsharghi, H., and Oldfors, A. (2009) TPM3 Mutation in One of the Original Cases of Cap Disease. Neurology. 72, 1961-1963.

6. Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., and North, K. N. (2008) Mutations in TPM3 are a Common Cause of Congenital Fiber Type Disproportion. Ann Neurol. 63, 329-337.

7. Wattanasirichaigoon, D., Swoboda, K. J., Takada, F., Tong, H. Q., Lip, V., Iannaccone, S. T., Wallgren-Pettersson, C., Laing, N. G., and Beggs, A. H. (2002) Mutations of the Slow Muscle Alpha-Tropomyosin Gene, TPM3, are a Rare Cause of Nemaline Myopathy. Neurology. 59, 613-617.

8. Tan, P., Briner, J., Boltshauser, E., Davis, M. R., Wilton, S. D., North, K., Wallgren-Pettersson, C., and Laing, N. G. (1999) Homozygosity for a Nonsense Mutation in the Alpha-Tropomyosin Slow Gene TPM3 in a Patient with Severe Infantile Nemaline Myopathy. Neuromuscul Disord. 9, 573-579.

9. Corbett, M. A., Robinson, C. S., Dunglison, G. F., Yang, N., Joya, J. E., Stewart, A. W., Schnell, C., Gunning, P. W., North, K. N., and Hardeman, E. C. (2001) A Mutation in Alpha-Tropomyosin(Slow) Affects Muscle Strength, Maturation and Hypertrophy in a Mouse Model for Nemaline Myopathy. Hum Mol Genet. 10, 317-328.

Posted On

2012-11-20

Science Writer

Anne Murray