Phenotypic Mutation 'Typhoon' (pdf version)
AlleleTyphoon
Mutation Type critical splice donor site
Chromosome11
Coordinate60,378,251 bp (GRCm39)
Base Change G ⇒ A (forward strand)
Gene Myo15a
Gene Name myosin XVA
Synonym(s) Myo15
Chromosomal Location 60,360,165-60,419,195 bp (+) (GRCm39)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mutations in this gene result in profound deafness and neurological behavior. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_010862NM_182698NM_001103171; MGI:1261811

MappedYes 
Amino Acid Change
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000071777 ] [ENSMUSP00000080507 ] [ENSMUSP00000091686 ]   † probably from a misspliced transcript
AlphaFold no structure available at present
SMART Domains Protein: ENSMUSP00000071777
Gene: ENSMUSG00000042678

DomainStartEndE-ValueType
low complexity region 4 24 N/A INTRINSIC
low complexity region 87 100 N/A INTRINSIC
low complexity region 107 120 N/A INTRINSIC
low complexity region 269 292 N/A INTRINSIC
low complexity region 295 306 N/A INTRINSIC
low complexity region 311 325 N/A INTRINSIC
low complexity region 349 384 N/A INTRINSIC
low complexity region 425 435 N/A INTRINSIC
low complexity region 487 498 N/A INTRINSIC
low complexity region 502 509 N/A INTRINSIC
low complexity region 653 681 N/A INTRINSIC
low complexity region 692 705 N/A INTRINSIC
low complexity region 737 747 N/A INTRINSIC
low complexity region 758 775 N/A INTRINSIC
low complexity region 781 792 N/A INTRINSIC
low complexity region 796 809 N/A INTRINSIC
low complexity region 825 849 N/A INTRINSIC
low complexity region 883 897 N/A INTRINSIC
low complexity region 1067 1082 N/A INTRINSIC
low complexity region 1115 1130 N/A INTRINSIC
MYSc 1200 1884 N/A SMART
IQ 1885 1907 1.63e-1 SMART
IQ 1908 1930 1.77e-2 SMART
IQ 1931 1953 2.97e2 SMART
low complexity region 1955 1974 N/A INTRINSIC
low complexity region 1992 2006 N/A INTRINSIC
MyTH4 2049 2195 1.8e-42 SMART
low complexity region 2396 2405 N/A INTRINSIC
low complexity region 2451 2461 N/A INTRINSIC
Blast:MYSc 2665 2848 2e-14 BLAST
SH3 2851 2933 1.55e-4 SMART
low complexity region 2949 2962 N/A INTRINSIC
MyTH4 3031 3185 5.59e-48 SMART
B41 3188 3400 6.94e-3 SMART
Predicted Effect probably null
SMART Domains Protein: ENSMUSP00000080507
Gene: ENSMUSG00000042678

DomainStartEndE-ValueType
MYSc 13 697 N/A SMART
IQ 698 720 1.63e-1 SMART
IQ 721 743 1.77e-2 SMART
IQ 744 766 2.97e2 SMART
low complexity region 787 801 N/A INTRINSIC
MyTH4 844 990 1.8e-42 SMART
low complexity region 1191 1200 N/A INTRINSIC
low complexity region 1246 1256 N/A INTRINSIC
Blast:MYSc 1460 1643 7e-15 BLAST
SH3 1646 1728 1.55e-4 SMART
low complexity region 1744 1757 N/A INTRINSIC
MyTH4 1826 1980 5.59e-48 SMART
B41 1983 2195 6.94e-3 SMART
Predicted Effect probably null
SMART Domains Protein: ENSMUSP00000091686
Gene: ENSMUSG00000042678

DomainStartEndE-ValueType
low complexity region 4 24 N/A INTRINSIC
low complexity region 87 100 N/A INTRINSIC
low complexity region 107 120 N/A INTRINSIC
low complexity region 269 292 N/A INTRINSIC
low complexity region 295 306 N/A INTRINSIC
low complexity region 311 325 N/A INTRINSIC
low complexity region 349 384 N/A INTRINSIC
low complexity region 425 435 N/A INTRINSIC
low complexity region 487 498 N/A INTRINSIC
low complexity region 502 509 N/A INTRINSIC
low complexity region 653 681 N/A INTRINSIC
low complexity region 692 705 N/A INTRINSIC
low complexity region 737 747 N/A INTRINSIC
low complexity region 758 775 N/A INTRINSIC
low complexity region 781 792 N/A INTRINSIC
low complexity region 796 809 N/A INTRINSIC
low complexity region 825 849 N/A INTRINSIC
low complexity region 883 897 N/A INTRINSIC
low complexity region 1067 1082 N/A INTRINSIC
low complexity region 1115 1130 N/A INTRINSIC
MYSc 1200 1884 N/A SMART
IQ 1885 1907 1.63e-1 SMART
IQ 1908 1930 1.77e-2 SMART
IQ 1931 1953 2.97e2 SMART
low complexity region 1974 1988 N/A INTRINSIC
MyTH4 2031 2177 1.8e-42 SMART
low complexity region 2378 2387 N/A INTRINSIC
low complexity region 2433 2443 N/A INTRINSIC
Blast:MYSc 2647 2830 2e-14 BLAST
SH3 2833 2915 1.55e-4 SMART
low complexity region 2931 2944 N/A INTRINSIC
MyTH4 3013 3167 5.59e-48 SMART
B41 3170 3382 6.94e-3 SMART
Predicted Effect probably null
SMART Domains Protein: ENSMUSP00000120839
Gene: ENSMUSG00000042678

DomainStartEndE-ValueType
MYSc 34 716 N/A SMART
IQ 717 739 1.63e-1 SMART
IQ 740 762 1.77e-2 SMART
IQ 763 785 2.97e2 SMART
low complexity region 806 820 N/A INTRINSIC
MyTH4 863 1009 1.8e-42 SMART
low complexity region 1210 1219 N/A INTRINSIC
low complexity region 1265 1275 N/A INTRINSIC
Blast:MYSc 1479 1662 5e-15 BLAST
SH3 1665 1747 1.55e-4 SMART
low complexity region 1763 1776 N/A INTRINSIC
Predicted Effect probably null
Meta Mutation Damage Score 0.9496 question?
Is this an essential gene? Non Essential (E-score: 0.000) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance  
Alleles Listed at MGI

All alleles(13) : Targeted(6) Spontaneous(2) Chemically induced (ENU)(3) Chemically induced (other) (1) Radiation induced(1)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00845:Myo15a APN 11 60368605 missense probably damaging 1.00
IGL01011:Myo15a APN 11 60367818 missense probably benign 0.33
IGL01100:Myo15a APN 11 60401984 missense probably damaging 1.00
IGL01357:Myo15a APN 11 60393115 splice site probably benign
IGL01634:Myo15a APN 11 60386298 missense probably damaging 1.00
IGL01763:Myo15a APN 11 60412564 missense probably benign 0.07
IGL01901:Myo15a APN 11 60418260 utr 3 prime probably benign
IGL01931:Myo15a APN 11 60386964 missense probably damaging 1.00
IGL02006:Myo15a APN 11 60401954 missense probably damaging 1.00
IGL02041:Myo15a APN 11 60397689 missense probably damaging 0.99
IGL02094:Myo15a APN 11 60401473 unclassified probably benign
IGL02122:Myo15a APN 11 60374292 missense probably benign 0.23
IGL02153:Myo15a APN 11 60389223 missense probably damaging 1.00
IGL02328:Myo15a APN 11 60417433 missense probably benign 0.13
IGL02330:Myo15a APN 11 60367987 missense possibly damaging 0.94
IGL02431:Myo15a APN 11 60401465 missense possibly damaging 0.73
IGL02639:Myo15a APN 11 60369447 missense probably benign
IGL02659:Myo15a APN 11 60382609 splice site probably benign
IGL02800:Myo15a APN 11 60393195 missense probably damaging 1.00
IGL02812:Myo15a APN 11 60368005 missense probably benign 0.15
IGL02863:Myo15a APN 11 60368953 missense probably damaging 1.00
IGL02873:Myo15a APN 11 60374308 missense probably damaging 1.00
IGL02990:Myo15a APN 11 60370266 missense probably benign 0.02
IGL03011:Myo15a APN 11 60400357 splice site probably benign
IGL03243:Myo15a APN 11 60387344 missense probably damaging 1.00
IGL03297:Myo15a APN 11 60369967 missense probably damaging 1.00
novichok UTSW 11 60372566 critical splice donor site probably null
parker UTSW 11 60411740 critical splice donor site probably null
PIT4131001:Myo15a UTSW 11 60386280 missense probably damaging 1.00
PIT4131001:Myo15a UTSW 11 60373953 missense probably damaging 1.00
R0133:Myo15a UTSW 11 60368676 missense possibly damaging 0.94
R0265:Myo15a UTSW 11 60405723 critical splice acceptor site probably null
R0389:Myo15a UTSW 11 60369364 missense probably benign
R0416:Myo15a UTSW 11 60402000 missense probably damaging 1.00
R0449:Myo15a UTSW 11 60400422 missense possibly damaging 0.92
R0477:Myo15a UTSW 11 60411740 critical splice donor site probably null
R0543:Myo15a UTSW 11 60369877 missense probably benign
R0546:Myo15a UTSW 11 60397139 missense probably damaging 1.00
R0555:Myo15a UTSW 11 60412464 missense probably damaging 1.00
R0639:Myo15a UTSW 11 60370162 missense probably benign 0.12
R0723:Myo15a UTSW 11 60369803 missense possibly damaging 0.94
R0837:Myo15a UTSW 11 60378077 missense probably damaging 0.98
R0865:Myo15a UTSW 11 60382514 missense probably damaging 1.00
R0899:Myo15a UTSW 11 60368011 missense possibly damaging 0.87
R1022:Myo15a UTSW 11 60370442 missense probably benign 0.00
R1024:Myo15a UTSW 11 60370442 missense probably benign 0.00
R1035:Myo15a UTSW 11 60401384 unclassified probably benign
R1109:Myo15a UTSW 11 60383892 missense probably damaging 1.00
R1170:Myo15a UTSW 11 60370233 missense probably benign 0.04
R1241:Myo15a UTSW 11 60390256 missense possibly damaging 0.58
R1392:Myo15a UTSW 11 60368800 missense possibly damaging 0.95
R1392:Myo15a UTSW 11 60368800 missense possibly damaging 0.95
R1434:Myo15a UTSW 11 60395157 missense probably benign 0.00
R1450:Myo15a UTSW 11 60386308 missense probably damaging 1.00
R1456:Myo15a UTSW 11 60399028 missense probably damaging 1.00
R1468:Myo15a UTSW 11 60396832 missense probably damaging 1.00
R1468:Myo15a UTSW 11 60396832 missense probably damaging 1.00
R1548:Myo15a UTSW 11 60379064 missense probably damaging 1.00
R1551:Myo15a UTSW 11 60383791 missense possibly damaging 0.70
R1571:Myo15a UTSW 11 60409290 missense probably damaging 1.00
R1662:Myo15a UTSW 11 60392527 missense probably damaging 1.00
R1777:Myo15a UTSW 11 60405762 missense probably benign
R1778:Myo15a UTSW 11 60369238 missense possibly damaging 0.57
R1847:Myo15a UTSW 11 60390321 nonsense probably null
R1875:Myo15a UTSW 11 60398354 missense probably damaging 0.99
R1944:Myo15a UTSW 11 60392909 missense probably damaging 0.99
R1945:Myo15a UTSW 11 60392909 missense probably damaging 0.99
R2013:Myo15a UTSW 11 60385057 missense probably damaging 1.00
R2107:Myo15a UTSW 11 60382636 missense probably damaging 1.00
R2108:Myo15a UTSW 11 60382636 missense probably damaging 1.00
R2112:Myo15a UTSW 11 60384994 missense probably damaging 0.99
R2147:Myo15a UTSW 11 60401055 missense possibly damaging 0.66
R2196:Myo15a UTSW 11 60400847 nonsense probably null
R2207:Myo15a UTSW 11 60396860 missense probably benign 0.01
R2245:Myo15a UTSW 11 60399925 missense probably damaging 1.00
R2367:Myo15a UTSW 11 60408064 missense probably damaging 0.99
R2374:Myo15a UTSW 11 60369669 missense possibly damaging 0.88
R2438:Myo15a UTSW 11 60373878 missense probably damaging 1.00
R3154:Myo15a UTSW 11 60370186 splice site probably null
R3423:Myo15a UTSW 11 60401126 critical splice donor site probably null
R3551:Myo15a UTSW 11 60400489 missense possibly damaging 0.93
R3552:Myo15a UTSW 11 60400489 missense possibly damaging 0.93
R3612:Myo15a UTSW 11 60368505 missense probably damaging 1.00
R3620:Myo15a UTSW 11 60369468 missense possibly damaging 0.63
R3713:Myo15a UTSW 11 60370057 missense possibly damaging 0.55
R3714:Myo15a UTSW 11 60370057 missense possibly damaging 0.55
R3715:Myo15a UTSW 11 60370057 missense possibly damaging 0.55
R3783:Myo15a UTSW 11 60368398 missense probably damaging 0.97
R3784:Myo15a UTSW 11 60368398 missense probably damaging 0.97
R3785:Myo15a UTSW 11 60368398 missense probably damaging 0.97
R3786:Myo15a UTSW 11 60368398 missense probably damaging 0.97
R3787:Myo15a UTSW 11 60368398 missense probably damaging 0.97
R3894:Myo15a UTSW 11 60395145 missense probably benign 0.00
R3962:Myo15a UTSW 11 60370654 missense probably benign 0.00
R4082:Myo15a UTSW 11 60378022 missense possibly damaging 0.92
R4555:Myo15a UTSW 11 60387763 missense probably damaging 1.00
R4641:Myo15a UTSW 11 60393867 missense probably damaging 1.00
R4665:Myo15a UTSW 11 60395705 critical splice acceptor site probably null
R4713:Myo15a UTSW 11 60370756 missense probably benign 0.21
R4820:Myo15a UTSW 11 60367741 missense probably damaging 0.98
R5013:Myo15a UTSW 11 60382493 missense probably damaging 1.00
R5051:Myo15a UTSW 11 60378251 critical splice donor site probably null
R5187:Myo15a UTSW 11 60394440 missense probably damaging 1.00
R5230:Myo15a UTSW 11 60393674 missense possibly damaging 0.68
R5277:Myo15a UTSW 11 60367940 nonsense probably null
R5345:Myo15a UTSW 11 60388364 missense probably damaging 0.99
R5349:Myo15a UTSW 11 60384409 missense probably damaging 1.00
R5356:Myo15a UTSW 11 60389192 missense probably damaging 1.00
R5445:Myo15a UTSW 11 60411603 nonsense probably null
R5477:Myo15a UTSW 11 60368503 missense probably damaging 1.00
R5629:Myo15a UTSW 11 60370578 missense probably benign
R5728:Myo15a UTSW 11 60379722 missense probably damaging 1.00
R5818:Myo15a UTSW 11 60388777 missense probably benign 0.06
R5952:Myo15a UTSW 11 60370246 missense possibly damaging 0.50
R6338:Myo15a UTSW 11 60368959 missense probably damaging 0.99
R6467:Myo15a UTSW 11 60417487 critical splice donor site probably null
R6488:Myo15a UTSW 11 60369313 missense possibly damaging 0.86
R6521:Myo15a UTSW 11 60393195 missense probably damaging 1.00
R6645:Myo15a UTSW 11 60368118 missense probably benign 0.00
R6702:Myo15a UTSW 11 60383818 missense probably benign 0.16
R6703:Myo15a UTSW 11 60383818 missense probably benign 0.16
R6821:Myo15a UTSW 11 60415301 missense probably damaging 1.00
R6882:Myo15a UTSW 11 60414832 missense probably damaging 1.00
R6908:Myo15a UTSW 11 60396832 missense probably damaging 1.00
R6932:Myo15a UTSW 11 60390320 missense probably damaging 1.00
R6958:Myo15a UTSW 11 60394451 missense probably benign 0.07
R7041:Myo15a UTSW 11 60396832 missense probably damaging 1.00
R7149:Myo15a UTSW 11 60400836 missense possibly damaging 0.56
R7163:Myo15a UTSW 11 60389195 missense
R7229:Myo15a UTSW 11 60387321 missense probably benign 0.08
R7347:Myo15a UTSW 11 60368787 missense probably benign
R7368:Myo15a UTSW 11 60381741 splice site probably null
R7392:Myo15a UTSW 11 60396802 missense
R7414:Myo15a UTSW 11 60374309 missense
R7461:Myo15a UTSW 11 60395978 missense
R7609:Myo15a UTSW 11 60379637 missense
R7613:Myo15a UTSW 11 60395978 missense
R7734:Myo15a UTSW 11 60401108 missense probably benign
R7748:Myo15a UTSW 11 60395727 missense
R7767:Myo15a UTSW 11 60392922 missense
R7769:Myo15a UTSW 11 60399975 missense
R7894:Myo15a UTSW 11 60381963 missense
R7919:Myo15a UTSW 11 60417356 missense probably damaging 1.00
R8100:Myo15a UTSW 11 60408016 missense probably damaging 1.00
R8124:Myo15a UTSW 11 60398279 missense
R8129:Myo15a UTSW 11 60399026 missense
R8428:Myo15a UTSW 11 60387241 missense probably damaging 1.00
R8706:Myo15a UTSW 11 60370443 missense probably benign
R8735:Myo15a UTSW 11 60401679 critical splice acceptor site probably null
R8739:Myo15a UTSW 11 60368088 missense probably benign 0.06
R8790:Myo15a UTSW 11 60378047 missense
R8790:Myo15a UTSW 11 60367362 missense possibly damaging 0.73
R8822:Myo15a UTSW 11 60367740 missense probably damaging 0.99
R8907:Myo15a UTSW 11 60417434 missense
R8931:Myo15a UTSW 11 60368020 missense probably benign
R9061:Myo15a UTSW 11 60393692 missense
R9124:Myo15a UTSW 11 60369952 missense probably benign 0.37
R9297:Myo15a UTSW 11 60385899 missense probably null
R9347:Myo15a UTSW 11 60374555 missense
R9417:Myo15a UTSW 11 60378243 missense
R9456:Myo15a UTSW 11 60392668 missense
R9460:Myo15a UTSW 11 60372566 critical splice donor site probably null
R9615:Myo15a UTSW 11 60374320 missense
R9630:Myo15a UTSW 11 60407988 missense probably damaging 1.00
R9746:Myo15a UTSW 11 60378234 nonsense probably null
X0021:Myo15a UTSW 11 60373185 nonsense probably null
X0066:Myo15a UTSW 11 60369046 missense probably damaging 1.00
X0067:Myo15a UTSW 11 60369444 missense possibly damaging 0.88
Z1176:Myo15a UTSW 11 60389229 missense
Z1176:Myo15a UTSW 11 60379084 missense
Z1176:Myo15a UTSW 11 60415267 missense probably damaging 1.00
Z1177:Myo15a UTSW 11 60386301 missense
Z1177:Myo15a UTSW 11 60379663 missense
Z1177:Myo15a UTSW 11 60368349 missense probably damaging 1.00
Mode of Inheritance Autosomal Recessive
Local Stock Live Mice
Repository
Last Updated 2019-10-23 1:57 PM by Anne Murray
Record Created 2017-02-16 8:48 AM by Jamie Russell
Record Posted 2017-03-03
Phenotypic Description

Figure 1. The typhoon mice exhibit ataxia and head tilt.

The typhoon phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5051, some of which showed ataxia and a head tilt (Figure 1). Some mice also ran in circles.

Nature of Mutation

Figure 2. Linkage mapping of the behavioral phenotypes using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 54 mutations (X-axis) identified in the G1 male of pedigree R5051. Phenotype data are shown for single locus linkage analysis without consideration of G2 dam identity.  Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.

Whole exome HiSeq sequencing of the G1 grandsire identified 54 mutations. The behavioral phenotypes were linked to two genes: Nlrp3 and Myo15. However, the mutation in Myo15 was presumed to be causative because the typhoon behavior phenotypes mimic other known alleles of Myo15 (see MGI for a list of Myo15 alleles as well as the entry for parker). The mutation in Myo15 a G to A transition at base pair 60,487,425(v38) on chromosome 11, or base pair 113,685 in the GenBank genomic region NC_000077 encoding Myo15; the mutation is within the donor splice site of intron 10.  Linkage was found with a recessive model of inheritance (P = 1.981 x 10-5), wherein four variant homozygotes departed phenotypically from 20 homozygous reference mice and 18 heterozygous mice with (Figure 2).  A substantial semidominant effect was also observed (P = 4.274 x 10-5). 

The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in the use of a cryptic site in intron 10, resulting in a transcript that has an 8-base pair insertion on intron 10. This predicts a frame shifted protein product beginning after amino acid 1,386 of the protein, which is normally 3,511 amino acids in length, and terminating after the inclusion of 23 aberrant amino acids.


 
         <--exon 9     <--exon 10 intron 10-->             <--exon 11-->
17906 ……TTTCTAGAAGG ……ATTGTGTTCCAG gtaggcaggtcagag…… GCCAAAAATGAAA……TCCCTGCTCAACTAA…… 18927
1362  ……-F--L--E--G ……-I--V--F--Q-                   --P--K--M--K-……-S--L--L--N--*- 

                 correct                                       aberrant


 

The donor splice site of intron 10, which is destroyed by the typhoon mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.

Illustration of Mutations in
Gene & Protein
Protein Prediction

Figure 3. Domain structure of myosin XV. At its N-terminus, myosin XV has an N-terminal extension (NTE); isoform 3 does not have the NTE. Within the motor domain, myosin XV has an ATP- and actin-binding site. Two IQ motifs are located within the neck of myosin XV. The C-terminal tail contains two myosin tail homology 4 (MyTH4) domains, a Src homology 3 (SH3) domain, and a 4.1/ezrin/radixin/moesin (FERM) domain. A FERM-like domain is predicted based on sequence similarity to one in human myosin VIIa, however, the precise location in mouse myosin XV has not been documented. At the C-terminus, myosin XV has a PDZ-ligand motif (ITLL*). The typhoon mutation (red asterisk) is located in the donor splice site of intron 10. See the text for more details.

Myo15 encodes myosin XV (alternatively, Myosin XVa), a 3,511 amino acid member of the unconventional myosin family. Myosin XV has a proline-rich N-terminal extension that does not have sequence similarity to reported proteins and the function is unknown [Figure 3; amino acids 1-1200; SMART; (1-3)]. Myosin XV has a highly conserved motor domain (amino acids 1200-1884; NM_010862SMART) following the N-terminal extension (2). The motor domain contains an adenosine triphosphate (ATP)- and an actin-binding site (amino acids 1299-1306 and 1776-1783, respectively; Uniprot) (4-6). The myosin neck region contains a variable number of light-chain binding (IQ) motifs (IQxxxRGxxxRK) and is linked to the motor domain by a converter region [(7); reviewed in (8;9)]. Myosin XV has two IQ motifs (amino acids 1909-1920; LQRCLRGFFIKR and amino acids 1932-1943; LQSRARGYLARQ) (5;8;9). The IQ motif is an α-helical structure that often mediates the binding of myosins to calmodulin, members of the EF-hand family of calcium-binding proteins, or myosin light chains [reviewed in (8;9)]. The myosin XV tail region is 1584 amino acids in length and has two myosin tail homology 4 (MyTH4) domains (amino acids 2049-2195 and 3031-3185; SMART), a band 4.1/ezrin/radixin/moesin (FERM)-like domain (amino acids 2687-2867, human myosin XVa), a Src homology 3 (SH3) domain (amino acids 2851-2933), and a FERM domain (alternatively, talin-like domain; amino acids 3188-3400) (1;2;10;11). The MyTH4 domain is proposed to function in microtubule binding as well as in actin binding to the plasma membrane (12). The FERM domain of myosin XV is proposed to be involved in anchoring myosin XV to the cell membrane (1). The function of the myosin XV SH3 domain is unknown, but it is proposed to mediate an intramolecular interaction with a region in the proline-rich N-terminal extension to regulate the activity of myosin XV (2). Myosin XV is unique among the myosins in that it has a predicted class I PDZ-ligand motif (ITLL*) at the C-terminus (11;13;14). The PDZ-ligand motif of myosin XV is required for association of myosin XV with whirlin as well as the localization of whirlin to stereocilia tips (13;15).

The typhoon mutation is predicted to result in a frame-shift and coding of a premature stop codon within exon 10. Premature truncation of myosin XV within exon 10 would result in loss in a portion of the motor domain and the domains following the motor domain.

Putative Mechanism

Myosin XV functions in the assembly and maintenance of actin organization in hair cells of the inner ear by acting as a motor and carrier along the length of the actin filament within the hair cells (16). Myosin XV senses the tension between the plasma membrane and the actin filaments, a function that is necessary in the growth of the steocilia (11). Myosin XV contributes to the elongation of stereocilia by delivering whirlin, a multi-PDZ domain-containing scaffold protein, to the stereocilia tips (13). Both myosin XV and whirlin are required for the elongation and staircase formation of the stereocilia bundle and myosin XV and whirlin may function as part of a complex that modulates the growth of actin bundles in the stereocilia (11;13). Another proposed function of myosin XV is the maintenance of the hair cell mechanotransduction apparatus at the tips of the stereocilia (4;13). Two myosin XV mutant mouse models, shaker 2 (Myo15sh2; MGI:1857036) and shaker 2(Myo15sh2J; MGI:1889795) have been characterized. Both the shaker 2 and shaker 2J mice have abnormally short stereocilia bundles on the inner ear hair cells compared to wild-type mice; the bundles are correctly positioned (1;4). As a result, the shaker 2 and shaker 2J homozygous mice are congenitally deaf and exhibit vestibular defects that cause head-tossing and circling behavior (2-4). Similar to the shaker 2J mice, the typhoon mice exhibit head-tossing and circling behavior. Anderson et al. propose that the myosin XVshaker 2J protein is unable to exert force on the actin cytoskeleton because the truncated protein is improperly anchored, resulting in a failure to form the scaffolding to form the normal stereocilia structure (1).  

Primers PCR Primer
Typhoon_pcr_F: AGGAATGACAACTCCAGCCG
Typhoon_pcr_R: AAGTGACAGGTTGCAGGCTC

Sequencing Primer
Typhoon_seq_F: GAATGACAACTCCAGCCGCTTTG
Typhoon_seq_R: TTGCAGGCTCAGGAACAC
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 401 nucleotides is amplified (chromosome 11, + strand):


1   aggaatgaca actccagccg ctttgggaag tttgtggaaa tctttctaga agggtgagtg
61  ggactgtggc agattctcag aggccctgca gagcccttgg tggcccacag cagcatccaa
121 ggccacctca gtctccaaga tctgactgtt ctttcccagg ggtgtgatct gtggtgccat
181 aacctctcag tacctgctgg agaagtcaag gattgtgttc caggtaggca ggtcagaggc
241 ctgagtggca ccaacactca tgtgtataca tgtggatgga tggatggata gatggataga
301 tagatagata gatagataga tagatagata gatagataga tagacagaca gactctgtga
361 atgcatgctg tctgtgttcc tgagcctgca acctgtcact t


Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.

References
Science Writers Anne Murray
Illustrators Katherine Timer
AuthorsLauren Prince, Jamie Russell, and Bruce Beutler