Phenotypic Mutation 'torticollis' (pdf version)
Allele | torticollis |
Mutation Type |
critical splice donor site
(1 bp from exon)
|
Chromosome | 9 |
Coordinate | 80,195,499 bp (GRCm39) |
Base Change | G ⇒ A (forward strand) |
Gene |
Myo6
|
Gene Name | myosin VI |
Synonym(s) | Myo6, Tlc, rsv |
Chromosomal Location |
80,072,313-80,219,011 bp (+) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014] PHENOTYPE: Homozygous mutant mice exhibit deafness and related behavioral characteristics such as circling, head tossing and hyperactivity. Progressive degeneration of the cochlear hair cells and the organ of Corti is observed with one mutation. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_001039546; MGI: 104785
|
Mapped | Yes |
Amino Acid Change |
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000036181 †]
[ENSMUSP00000075501 †]
[ENSMUSP00000108891 †]
[ENSMUSP00000108893 †]
[ENSMUSP00000139228 †]
[ENSMUSP00000139019 †]
† probably from a misspliced transcript
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000036181 Gene: ENSMUSG00000033577
Domain | Start | End | E-Value | Type |
MYSc
|
51 |
772 |
N/A |
SMART |
IQ
|
812 |
834 |
8.58e-1 |
SMART |
low complexity region
|
909 |
980 |
N/A |
INTRINSIC |
low complexity region
|
982 |
1002 |
N/A |
INTRINSIC |
Blast:MYSc
|
1003 |
1113 |
3e-29 |
BLAST |
PDB:3H8D|D
|
1134 |
1262 |
1e-74 |
PDB |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000075501 Gene: ENSMUSG00000033577
Domain | Start | End | E-Value | Type |
MYSc
|
51 |
772 |
N/A |
SMART |
IQ
|
812 |
834 |
8.58e-1 |
SMART |
low complexity region
|
909 |
980 |
N/A |
INTRINSIC |
low complexity region
|
982 |
1002 |
N/A |
INTRINSIC |
Blast:MYSc
|
1003 |
1126 |
2e-27 |
BLAST |
PDB:3H8D|D
|
1138 |
1266 |
8e-75 |
PDB |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000108891 Gene: ENSMUSG00000033577
Domain | Start | End | E-Value | Type |
MYSc
|
51 |
772 |
N/A |
SMART |
IQ
|
812 |
834 |
8.58e-1 |
SMART |
low complexity region
|
909 |
980 |
N/A |
INTRINSIC |
low complexity region
|
982 |
1002 |
N/A |
INTRINSIC |
Blast:MYSc
|
1003 |
1113 |
3e-29 |
BLAST |
PDB:3H8D|D
|
1125 |
1253 |
9e-75 |
PDB |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000108893 Gene: ENSMUSG00000033577
Domain | Start | End | E-Value | Type |
MYSc
|
51 |
772 |
N/A |
SMART |
IQ
|
812 |
834 |
8.58e-1 |
SMART |
low complexity region
|
909 |
980 |
N/A |
INTRINSIC |
low complexity region
|
982 |
1002 |
N/A |
INTRINSIC |
Blast:MYSc
|
1003 |
1135 |
2e-26 |
BLAST |
Pfam:Myosin-VI_CBD
|
1167 |
1257 |
1.4e-46 |
PFAM |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000139228 Gene: ENSMUSG00000033577
Domain | Start | End | E-Value | Type |
MYSc
|
51 |
772 |
N/A |
SMART |
IQ
|
812 |
834 |
8.58e-1 |
SMART |
low complexity region
|
909 |
980 |
N/A |
INTRINSIC |
low complexity region
|
982 |
1002 |
N/A |
INTRINSIC |
Blast:MYSc
|
1003 |
1136 |
1e-26 |
BLAST |
PDB:3H8D|D
|
1157 |
1285 |
9e-75 |
PDB |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000139019 Gene: ENSMUSG00000033577
Domain | Start | End | E-Value | Type |
MYSc
|
51 |
772 |
N/A |
SMART |
IQ
|
812 |
834 |
8.58e-1 |
SMART |
low complexity region
|
909 |
980 |
N/A |
INTRINSIC |
low complexity region
|
982 |
1002 |
N/A |
INTRINSIC |
Blast:MYSc
|
1003 |
1145 |
1e-25 |
BLAST |
PDB:3H8D|D
|
1166 |
1294 |
8e-75 |
PDB |
|
Predicted Effect |
probably null
|
Meta Mutation Damage Score |
0.9472 |
Is this an essential gene? |
Non Essential (E-score: 0.000) |
Phenotypic Category |
Autosomal Recessive |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All alleles(12) : Targeted(4) Gene trapped(1) Spontaneous(6) Chemically induced(1)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00493:Myo6
|
APN |
9 |
80199754 |
missense |
probably damaging |
0.98 |
IGL00584:Myo6
|
APN |
9 |
80149555 |
splice site |
probably benign |
|
IGL00596:Myo6
|
APN |
9 |
80189025 |
missense |
possibly damaging |
0.91 |
IGL00778:Myo6
|
APN |
9 |
80190868 |
critical splice donor site |
probably null |
|
IGL01667:Myo6
|
APN |
9 |
80197175 |
missense |
unknown |
|
IGL01939:Myo6
|
APN |
9 |
80168100 |
missense |
probably damaging |
1.00 |
IGL02123:Myo6
|
APN |
9 |
80171554 |
splice site |
probably benign |
|
IGL02271:Myo6
|
APN |
9 |
80168113 |
missense |
probably benign |
0.01 |
IGL02512:Myo6
|
APN |
9 |
80199801 |
critical splice donor site |
probably null |
|
IGL02716:Myo6
|
APN |
9 |
80176976 |
missense |
probably damaging |
1.00 |
IGL02888:Myo6
|
APN |
9 |
80177013 |
splice site |
probably benign |
|
IGL02890:Myo6
|
APN |
9 |
80173456 |
missense |
probably damaging |
1.00 |
IGL02951:Myo6
|
APN |
9 |
80171516 |
missense |
possibly damaging |
0.66 |
IGL02990:Myo6
|
APN |
9 |
80183685 |
critical splice donor site |
probably null |
|
IGL03060:Myo6
|
APN |
9 |
80168159 |
missense |
probably benign |
0.00 |
IGL03145:Myo6
|
APN |
9 |
80207947 |
nonsense |
probably null |
|
IGL03306:Myo6
|
APN |
9 |
80153837 |
missense |
probably damaging |
1.00 |
agnostic
|
UTSW |
9 |
80190816 |
missense |
possibly damaging |
0.62 |
knownothing
|
UTSW |
9 |
80210583 |
critical splice donor site |
probably null |
|
mayday_circler
|
UTSW |
9 |
80153733 |
nonsense |
probably null |
|
toss
|
UTSW |
9 |
80207949 |
critical splice donor site |
probably null |
|
truths
|
UTSW |
9 |
80177321 |
nonsense |
probably null |
|
unbiased
|
UTSW |
9 |
80181257 |
splice site |
probably benign |
|
IGL03134:Myo6
|
UTSW |
9 |
80199749 |
missense |
probably damaging |
0.96 |
R0023:Myo6
|
UTSW |
9 |
80190816 |
missense |
possibly damaging |
0.62 |
R0023:Myo6
|
UTSW |
9 |
80190816 |
missense |
possibly damaging |
0.62 |
R0124:Myo6
|
UTSW |
9 |
80215056 |
missense |
probably damaging |
1.00 |
R0133:Myo6
|
UTSW |
9 |
80181257 |
splice site |
probably benign |
|
R0207:Myo6
|
UTSW |
9 |
80195338 |
missense |
probably damaging |
1.00 |
R0295:Myo6
|
UTSW |
9 |
80190861 |
missense |
probably damaging |
0.98 |
R0389:Myo6
|
UTSW |
9 |
80199748 |
missense |
probably damaging |
0.98 |
R0432:Myo6
|
UTSW |
9 |
80181256 |
splice site |
probably benign |
|
R0526:Myo6
|
UTSW |
9 |
80190823 |
missense |
possibly damaging |
0.61 |
R0791:Myo6
|
UTSW |
9 |
80169656 |
splice site |
probably benign |
|
R0885:Myo6
|
UTSW |
9 |
80149503 |
missense |
probably damaging |
1.00 |
R1082:Myo6
|
UTSW |
9 |
80195303 |
missense |
probably damaging |
1.00 |
R1113:Myo6
|
UTSW |
9 |
80152996 |
missense |
probably damaging |
1.00 |
R1184:Myo6
|
UTSW |
9 |
80193664 |
nonsense |
probably null |
|
R1308:Myo6
|
UTSW |
9 |
80152996 |
missense |
probably damaging |
1.00 |
R1498:Myo6
|
UTSW |
9 |
80214961 |
missense |
probably damaging |
1.00 |
R1609:Myo6
|
UTSW |
9 |
80195499 |
critical splice donor site |
probably null |
|
R1615:Myo6
|
UTSW |
9 |
80215007 |
missense |
probably damaging |
1.00 |
R1771:Myo6
|
UTSW |
9 |
80193082 |
missense |
probably damaging |
1.00 |
R1772:Myo6
|
UTSW |
9 |
80177331 |
missense |
possibly damaging |
0.95 |
R1789:Myo6
|
UTSW |
9 |
80207854 |
missense |
probably damaging |
1.00 |
R1962:Myo6
|
UTSW |
9 |
80168117 |
missense |
probably damaging |
1.00 |
R1978:Myo6
|
UTSW |
9 |
80136207 |
missense |
probably damaging |
0.99 |
R2011:Myo6
|
UTSW |
9 |
80215004 |
missense |
probably damaging |
0.99 |
R2092:Myo6
|
UTSW |
9 |
80152964 |
missense |
probably damaging |
1.00 |
R2098:Myo6
|
UTSW |
9 |
80188808 |
missense |
probably damaging |
1.00 |
R2206:Myo6
|
UTSW |
9 |
80165737 |
missense |
probably benign |
0.01 |
R2286:Myo6
|
UTSW |
9 |
80173494 |
missense |
possibly damaging |
0.82 |
R2429:Myo6
|
UTSW |
9 |
80210583 |
critical splice donor site |
probably null |
|
R2696:Myo6
|
UTSW |
9 |
80168176 |
missense |
probably benign |
0.00 |
R2897:Myo6
|
UTSW |
9 |
80176893 |
splice site |
probably null |
|
R2898:Myo6
|
UTSW |
9 |
80176893 |
splice site |
probably null |
|
R3881:Myo6
|
UTSW |
9 |
80171538 |
missense |
probably damaging |
1.00 |
R4424:Myo6
|
UTSW |
9 |
80195320 |
missense |
probably benign |
0.26 |
R4718:Myo6
|
UTSW |
9 |
80153799 |
missense |
probably benign |
0.01 |
R4893:Myo6
|
UTSW |
9 |
80136159 |
missense |
probably damaging |
1.00 |
R4936:Myo6
|
UTSW |
9 |
80214963 |
missense |
probably damaging |
1.00 |
R4992:Myo6
|
UTSW |
9 |
80190792 |
missense |
possibly damaging |
0.95 |
R5073:Myo6
|
UTSW |
9 |
80195290 |
missense |
probably benign |
0.00 |
R5101:Myo6
|
UTSW |
9 |
80177321 |
nonsense |
probably null |
|
R5137:Myo6
|
UTSW |
9 |
80149531 |
missense |
probably damaging |
1.00 |
R5200:Myo6
|
UTSW |
9 |
80183656 |
nonsense |
probably null |
|
R5510:Myo6
|
UTSW |
9 |
80152942 |
missense |
probably damaging |
1.00 |
R5579:Myo6
|
UTSW |
9 |
80125002 |
missense |
probably damaging |
0.99 |
R5693:Myo6
|
UTSW |
9 |
80173462 |
missense |
probably damaging |
1.00 |
R5701:Myo6
|
UTSW |
9 |
80165809 |
missense |
probably damaging |
1.00 |
R6693:Myo6
|
UTSW |
9 |
80153013 |
missense |
probably damaging |
1.00 |
R7151:Myo6
|
UTSW |
9 |
80152418 |
missense |
unknown |
|
R7399:Myo6
|
UTSW |
9 |
80169573 |
missense |
unknown |
|
R7492:Myo6
|
UTSW |
9 |
80195328 |
nonsense |
probably null |
|
R7651:Myo6
|
UTSW |
9 |
80171548 |
critical splice donor site |
probably null |
|
R7698:Myo6
|
UTSW |
9 |
80124938 |
missense |
unknown |
|
R7743:Myo6
|
UTSW |
9 |
80183611 |
missense |
unknown |
|
R7888:Myo6
|
UTSW |
9 |
80203947 |
missense |
probably damaging |
0.99 |
R8161:Myo6
|
UTSW |
9 |
80124991 |
missense |
unknown |
|
R8245:Myo6
|
UTSW |
9 |
80162229 |
missense |
unknown |
|
R8375:Myo6
|
UTSW |
9 |
80162206 |
missense |
unknown |
|
R8387:Myo6
|
UTSW |
9 |
80183632 |
missense |
unknown |
|
R8467:Myo6
|
UTSW |
9 |
80136168 |
missense |
probably damaging |
1.00 |
R8669:Myo6
|
UTSW |
9 |
80173531 |
missense |
unknown |
|
R8770:Myo6
|
UTSW |
9 |
80171481 |
missense |
unknown |
|
R8807:Myo6
|
UTSW |
9 |
80207949 |
critical splice donor site |
probably null |
|
R9006:Myo6
|
UTSW |
9 |
80136140 |
missense |
unknown |
|
R9018:Myo6
|
UTSW |
9 |
80159086 |
missense |
unknown |
|
R9038:Myo6
|
UTSW |
9 |
80162285 |
missense |
unknown |
|
R9124:Myo6
|
UTSW |
9 |
80195353 |
missense |
unknown |
|
R9190:Myo6
|
UTSW |
9 |
80195384 |
missense |
unknown |
|
R9194:Myo6
|
UTSW |
9 |
80153836 |
missense |
unknown |
|
R9281:Myo6
|
UTSW |
9 |
80162164 |
nonsense |
probably null |
|
Z1191:Myo6
|
UTSW |
9 |
80149509 |
nonsense |
probably null |
|
|
Mode of Inheritance |
Autosomal Recessive |
Local Stock | Live Mice, gDNA |
MMRRC Submission |
038164-MU
|
Last Updated |
2019-09-04 9:47 PM
by Anne Murray
|
Record Created |
2014-12-18 5:54 PM
by Jeff SoRelle
|
Record Posted |
2015-02-12 |
Phenotypic Description |
The torticollis phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R1609, some of which showed increased locomotor activity, head tossing, and circling behavior (Figure 1).
|
Nature of Mutation | Whole exome HiSeq sequencing of the G1 grandsire identified 47 mutations. A mutation in Myo6 was presumed to be causative because the torticollis phenotype mirrored the mayday_circler phenotype attributed to Myo6 as well as other Myo6 alleles (see MGI). The mutation in Myo6 is a G to A transition at base pair 80,288,217 (v38) on chromosome 9, or base pair 123,242 in the GenBank genomic region NC_000075 within the donor splice site of intron 26. The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in skipping of the 209-nucleotide exon 26 (out of 33 total exons), resulting in a frame-shift and coding of two aberrant amino acids followed by a premature stop codon after amino acid 888.
<--exon 25 <--exon 26 intron 26--> exon 27-->
121443 ……ATGGCCAAAATTAAG……GAGGAGAGGCGGAT gtaagacatttgcattgt……GAAACTTGA
882 ……-M--A--K--I--K-……-E--E--R--R--M ……-E--T--*
correct deleted aberrant
|
The donor splice site of intron 26, which is destroyed by the torticollis mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
Myo6 encodes myosin VI, a member of the unconventional myosin family that function as actin-based molecular motors for various cellular cargoes, producing mechanical force through repeated cycles of ATP hydrolysis. Like other myosins, myosin VI has at its N-terminus a catalytic head with converter domain followed by a single canonical light chain-binding domain (Figure 2) (1;2). The myosin VI tail consists of a proximal tail domain (also called the lever arm extension, LAE), a medial tail domain (also called the single α-helix domain, SAH), and a globular cargo-binding domain. In mammalian cells, alternative splicing of the tail domain gives rise to four distinct myosin VI isoforms that may localize and function differentially in cells (3). The four isoforms contain either a large insert (21-31 amino acids) at the C-terminal end of the medial tail domain, a small insert (9 amino acids) within the cargo-binding domain, both inserts, or no insert. The torticollis mutation is predicted to result in coding of a premature stop codon within the proximal tail domain. Please see the record mayday_circler for information about Myo6.
|
Putative Mechanism | Myosin VI is involved in membrane trafficking, both exocytosis and endocytosis [reviewed in (4)]. MYO6 mutations have been linked with both dominant (OMIM #606346) (5) and recessive non-syndromic hearing loss (OMIM #607821) (6), as well as with dominant syndromic hearing loss that includes hypertrophic cardiomyopathy (7). A mutation in mouse myosin VI was implicated through positional cloning as the cause of Snell’s waltzer (sv) phenotype (8), which arose spontaneously in 1960 and is characterized by circling behavior, head tossing, deafness, and hyperactivity observable by 12 days of age (9). Although the appearance of hair cells and their stereocilia is relatively normal at birth in homozygous Myo6sv/sv mice, the stereocilia undergo progressive disorganization and a raising of the hair cell apical plasma membrane between stereocilia such that by three days of age all hair cells show fused stereocilia and by 20 days giant stereocilia are observed on top of hair cells (10). The formation of stereocilial branches is also observed at one day of age (11). By 6 weeks, there is a complete degeneration of both inner and outer hair cells within the Organ of Corti (8). The phenotype of the torticollis mice is consistent with a loss-of-function mutation in Myo6; the expression and localization of the myosin VItorticollis protein have not been examined.
|
Primers |
PCR Primer
torticollis_pcr_F: ACCATGATGACGAGGGAGCAGATAC
torticollis_pcr_R: GGCTACAAGGCCGACTCTAAACACTAA
Sequencing Primer
torticollis_seq_F: ATACAGAAAGAGTATGATGCACTTG
torticollis_seq_R: cttactcatacacacacacacac
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 203 nucleotides is amplified (chromosome 9, + strand):
1 accatgatga cgagggagca gatacagaaa gagtatgatg cacttgttaa aagctcagaa 61 gatctcctca gtgcactgca gaaaaagaaa cagcaagagg aggaggccga gaggctgagg 121 cgcatccagg aggagatgga gaaagaaagg aagaggcgtg aagaagatga ggaacgtcgg 181 cggaaggagg aagaggagag gcg
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References |
3. Buss, F., Arden, S. D., Lindsay, M., Luzio, J. P., and Kendrick-Jones, J. (2001) Myosin VI Isoform Localized to Clathrin-Coated Vesicles with a Role in Clathrin-Mediated Endocytosis. EMBO J. 20, 3676-3684.
5. Melchionda, S., Ahituv, N., Bisceglia, L., Sobe, T., Glaser, F., Rabionet, R., Arbones, M. L., Notarangelo, A., Di Iorio, E., Carella, M., Zelante, L., Estivill, X., Avraham, K. B., and Gasparini, P. (2001) MYO6, the Human Homologue of the Gene Responsible for Deafness in Snell's Waltzer Mice, is Mutated in Autosomal Dominant Nonsyndromic Hearing Loss. Am J Hum Genet. 69, 635-640.
6. Ahmed, Z. M., Morell, R. J., Riazuddin, S., Gropman, A., Shaukat, S., Ahmad, M. M., Mohiddin, S. A., Fananapazir, L., Caruso, R. C., Husnain, T., Khan, S. N., Riazuddin, S., Griffith, A. J., Friedman, T. B., and Wilcox, E. R. (2003) Mutations of MYO6 are Associated with Recessive Deafness, DFNB37. Am J Hum Genet. 72, 1315-1322.
7. Mohiddin, S. A., Ahmed, Z. M., Griffith, A. J., Tripodi, D., Friedman, T. B., Fananapazir, L., and Morell, R. J. (2004) Novel Association of Hypertrophic Cardiomyopathy, Sensorineural Deafness, and a Mutation in Unconventional Myosin VI (MYO6). J Med Genet. 41, 309-314.
8. Avraham, K. B., Hasson, T., Steel, K. P., Kingsley, D. M., Russell, L. B., Mooseker, M. S., Copeland, N. G., and Jenkins, N. A. (1995) The Mouse Snell's Waltzer Deafness Gene Encodes an Unconventional Myosin Required for Structural Integrity of Inner Ear Hair Cells. Nat Genet. 11, 369-375.
10. Self, T., Sobe, T., Copeland, N. G., Jenkins, N. A., Avraham, K. B., and Steel, K. P. (1999) Role of Myosin VI in the Differentiation of Cochlear Hair Cells. Dev Biol. 214, 331-341.
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Science Writers | Anne Murray |
Illustrators | Peter Jurek |
Authors | Jeff SoRelle, Zhe Chen, Doan Dao |