Phenotypic Mutation 'silver_decerebrate' (pdf version)
Allelesilver_decerebrate
Mutation Type missense
Chromosome9
Coordinate75,071,477 bp (GRCm39)
Base Change G ⇒ T (forward strand)
Gene Myo5a
Gene Name myosin VA
Synonym(s) flail, Myo5, MVa, Dbv, 9630007J19Rik, MyoVA
Chromosomal Location 74,978,297-75,130,970 bp (+) (GRCm39)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene is one of three myosin V heavy-chain genes, belonging to the myosin gene superfamily. Myosin V is a class of actin-based motor proteins involved in cytoplasmic vesicle transport and anchorage, spindle-pole alignment and mRNA translocation. The protein encoded by this gene is abundant in melanocytes and nerve cells. Mutations in this gene cause Griscelli syndrome type-1 (GS1), Griscelli syndrome type-3 (GS3) and neuroectodermal melanolysosomal disease, or Elejalde disease. Multiple alternatively spliced transcript variants encoding different isoforms have been reported, but the full-length nature of some variants has not been determined. [provided by RefSeq, Dec 2008]
PHENOTYPE: Mutations in this gene result in diluted coat color, behavioral deficits including opisthotonus, and postnatal or premature death. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_010864; MGI: 105976

MappedYes 
Amino Acid Change Serine changed to Isoleucine
Institutional SourceBeutler Lab
Gene Model not available
AlphaFold Q99104
PDB Structure Structure of apo-calmodulin bound to unconventional myosin V [X-RAY DIFFRACTION]
Crystal Structure of MyoVa-GTD [X-RAY DIFFRACTION]
Crystal Structure of MyoVa-GTD in Complex with Two Cargos [X-RAY DIFFRACTION]
SMART Domains Protein: ENSMUSP00000116028
Gene: ENSMUSG00000034593
AA Change: S693I

DomainStartEndE-ValueType
MYSc 63 764 N/A SMART
IQ 765 787 3.65e-4 SMART
IQ 788 810 1.56e-3 SMART
IQ 813 835 3.05e-6 SMART
IQ 836 858 8.38e-4 SMART
IQ 861 883 1.09e-2 SMART
IQ 884 906 6.97e0 SMART
coiled coil region 1153 1234 N/A INTRINSIC
coiled coil region 1314 1364 N/A INTRINSIC
coiled coil region 1406 1443 N/A INTRINSIC
DIL 1685 1790 2.47e-51 SMART
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000123128)
Predicted Effect probably benign
SMART Domains Protein: ENSMUSP00000120444
Gene: ENSMUSG00000034593
AA Change: S693I

DomainStartEndE-ValueType
MYSc 63 764 N/A SMART
IQ 765 787 3.65e-4 SMART
IQ 788 810 1.56e-3 SMART
IQ 813 835 3.05e-6 SMART
IQ 836 858 8.38e-4 SMART
IQ 861 883 1.09e-2 SMART
IQ 884 906 6.97e0 SMART
coiled coil region 1153 1234 N/A INTRINSIC
coiled coil region 1314 1418 N/A INTRINSIC
DIL 1660 1765 2.47e-51 SMART
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000136731)
SMART Domains Protein: ENSMUSP00000117493
Gene: ENSMUSG00000034593
AA Change: S693I

DomainStartEndE-ValueType
MYSc 63 764 N/A SMART
IQ 765 787 3.65e-4 SMART
IQ 788 810 1.56e-3 SMART
IQ 813 835 3.05e-6 SMART
IQ 836 858 8.38e-4 SMART
IQ 861 883 1.09e-2 SMART
IQ 884 906 6.97e0 SMART
coiled coil region 1153 1234 N/A INTRINSIC
coiled coil region 1339 1445 N/A INTRINSIC
DIL 1687 1792 2.47e-51 SMART
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000155282)
Meta Mutation Damage Score Not available question?
Is this an essential gene? Probably essential (E-score: 0.961) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance Probably 100% 
Alleles Listed at MGI

All alleles(71) : Gene trapped(2) Spontaneous(52) Chemically induced(17

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00090:Myo5a APN 9 75068779 nonsense probably null
IGL00547:Myo5a APN 9 75048735 missense probably benign 0.00
IGL00788:Myo5a APN 9 75076241 missense probably benign 0.15
IGL01327:Myo5a APN 9 75094820 splice site probably benign
IGL01687:Myo5a APN 9 75063531 missense probably benign 0.12
IGL01886:Myo5a APN 9 75076372 splice site probably benign
IGL01945:Myo5a APN 9 75047953 missense probably damaging 1.00
IGL02127:Myo5a APN 9 75120263 missense probably benign 0.12
IGL02137:Myo5a APN 9 75068817 splice site probably null
IGL02183:Myo5a APN 9 75074518 splice site probably benign
IGL02427:Myo5a APN 9 75083900 splice site probably benign
IGL02490:Myo5a APN 9 75043737 missense probably damaging 1.00
IGL02574:Myo5a APN 9 75118429 missense probably benign 0.00
IGL02886:Myo5a APN 9 75059169 splice site probably benign
IGL02961:Myo5a APN 9 75122402 missense probably benign 0.04
IGL03090:Myo5a APN 9 75028115 missense probably damaging 1.00
IGL03119:Myo5a APN 9 75081297 missense probably benign 0.01
IGL03237:Myo5a APN 9 75037276 missense probably damaging 1.00
IGL03296:Myo5a APN 9 75023484 missense probably damaging 1.00
naoki UTSW 9 75068774 missense probably damaging 1.00
new_gray UTSW 9 missense
nut UTSW 9 splice donor site
silver_decerebrate_2 UTSW 9 75118408 missense probably damaging 1.00
IGL02988:Myo5a UTSW 9 75037423 splice site probably benign
IGL03050:Myo5a UTSW 9 75054191 splice site probably null
PIT4403001:Myo5a UTSW 9 75124805 missense probably damaging 1.00
R0047:Myo5a UTSW 9 75063489 missense probably damaging 1.00
R0047:Myo5a UTSW 9 75063489 missense probably damaging 1.00
R0091:Myo5a UTSW 9 75068774 missense probably damaging 1.00
R0142:Myo5a UTSW 9 75067856 missense probably benign 0.01
R0243:Myo5a UTSW 9 75093405 critical splice donor site probably null
R0395:Myo5a UTSW 9 75101259 missense probably benign 0.39
R0427:Myo5a UTSW 9 75081478 missense probably benign 0.00
R0545:Myo5a UTSW 9 75074319 missense possibly damaging 0.94
R0565:Myo5a UTSW 9 75087394 missense probably benign 0.00
R0601:Myo5a UTSW 9 75081297 missense probably benign 0.01
R1457:Myo5a UTSW 9 75120347 missense probably damaging 0.99
R1510:Myo5a UTSW 9 75078833 missense probably benign
R1548:Myo5a UTSW 9 75079028 missense probably damaging 1.00
R1759:Myo5a UTSW 9 75089275 missense possibly damaging 0.72
R1924:Myo5a UTSW 9 75023489 missense probably damaging 1.00
R1960:Myo5a UTSW 9 75055139 missense probably damaging 1.00
R2050:Myo5a UTSW 9 75054156 missense probably benign 0.01
R2070:Myo5a UTSW 9 75089266 missense probably benign 0.03
R2075:Myo5a UTSW 9 75097200 missense probably benign 0.01
R2148:Myo5a UTSW 9 75087429 missense probably damaging 1.00
R2201:Myo5a UTSW 9 75125225 missense possibly damaging 0.51
R2337:Myo5a UTSW 9 75111083 missense probably damaging 1.00
R2357:Myo5a UTSW 9 75108647 missense probably damaging 0.99
R2392:Myo5a UTSW 9 75116521 missense probably benign 0.02
R2432:Myo5a UTSW 9 75120155 missense possibly damaging 0.89
R2568:Myo5a UTSW 9 75059179 missense probably damaging 1.00
R2568:Myo5a UTSW 9 75030322 missense probably damaging 1.00
R2932:Myo5a UTSW 9 75103418 missense possibly damaging 0.85
R2971:Myo5a UTSW 9 75023484 missense probably damaging 1.00
R4231:Myo5a UTSW 9 75097279 missense possibly damaging 0.67
R4293:Myo5a UTSW 9 75051453 missense probably benign
R4321:Myo5a UTSW 9 75124812 missense probably damaging 0.99
R4450:Myo5a UTSW 9 75074458 missense probably benign 0.00
R4573:Myo5a UTSW 9 75108579 splice site probably null
R4577:Myo5a UTSW 9 75124827 missense probably damaging 1.00
R4601:Myo5a UTSW 9 75043670 missense probably damaging 1.00
R4690:Myo5a UTSW 9 75061105 missense probably damaging 0.99
R4691:Myo5a UTSW 9 75087438 missense probably damaging 0.99
R4764:Myo5a UTSW 9 75023618 intron probably benign
R4767:Myo5a UTSW 9 75051358 missense probably damaging 0.99
R4811:Myo5a UTSW 9 75048825 critical splice donor site probably null
R4829:Myo5a UTSW 9 75043689 missense probably damaging 1.00
R4863:Myo5a UTSW 9 75124789 missense probably damaging 1.00
R4902:Myo5a UTSW 9 75081360 missense probably benign
R4947:Myo5a UTSW 9 75030330 missense probably damaging 1.00
R5074:Myo5a UTSW 9 75081438 missense probably benign
R5095:Myo5a UTSW 9 75091671 nonsense probably null
R5095:Myo5a UTSW 9 75059302 missense probably damaging 1.00
R5254:Myo5a UTSW 9 75037402 missense probably damaging 1.00
R5267:Myo5a UTSW 9 75059292 missense probably damaging 1.00
R5419:Myo5a UTSW 9 75055179 missense probably damaging 1.00
R5514:Myo5a UTSW 9 75061048 missense probably damaging 1.00
R5629:Myo5a UTSW 9 75111127 missense possibly damaging 0.89
R5649:Myo5a UTSW 9 75079001 missense possibly damaging 0.92
R5661:Myo5a UTSW 9 75074488 missense probably benign 0.02
R5665:Myo5a UTSW 9 75051463 critical splice donor site probably null
R5719:Myo5a UTSW 9 75059213 missense probably damaging 1.00
R5964:Myo5a UTSW 9 75111115 missense probably benign 0.09
R6014:Myo5a UTSW 9 75074489 nonsense probably null
R6344:Myo5a UTSW 9 75067791 missense probably benign 0.09
R6345:Myo5a UTSW 9 75097195 missense possibly damaging 0.77
R6644:Myo5a UTSW 9 75054249 missense probably damaging 0.98
R6712:Myo5a UTSW 9 75120182 missense probably benign 0.12
R6838:Myo5a UTSW 9 75061165 critical splice donor site probably null
R6866:Myo5a UTSW 9 75047970 missense probably damaging 1.00
R6876:Myo5a UTSW 9 75067772 missense probably benign 0.04
R7108:Myo5a UTSW 9 75037274 missense probably damaging 1.00
R7159:Myo5a UTSW 9 75078845 missense probably benign 0.07
R7164:Myo5a UTSW 9 75087435 missense probably benign 0.00
R7219:Myo5a UTSW 9 75028052 missense probably damaging 1.00
R7497:Myo5a UTSW 9 75104983 missense
R7620:Myo5a UTSW 9 75071418 missense probably benign 0.41
R7719:Myo5a UTSW 9 75051366 missense probably benign 0.01
R7810:Myo5a UTSW 9 75076292 missense probably benign
R7810:Myo5a UTSW 9 75067747 missense probably benign 0.09
R7866:Myo5a UTSW 9 75111034 missense probably damaging 1.00
R7939:Myo5a UTSW 9 75097182 missense
R8050:Myo5a UTSW 9 75089228 missense probably damaging 0.99
R8061:Myo5a UTSW 9 75030239 nonsense probably null
R8326:Myo5a UTSW 9 75125271 missense probably damaging 0.98
R8529:Myo5a UTSW 9 75120154 missense probably benign 0.02
R8824:Myo5a UTSW 9 75074328 missense probably damaging 1.00
R8858:Myo5a UTSW 9 75091965 missense probably damaging 0.99
R9040:Myo5a UTSW 9 75081341 missense probably benign 0.07
R9092:Myo5a UTSW 9 75054414 critical splice donor site probably null
R9249:Myo5a UTSW 9 75097279 missense possibly damaging 0.67
R9274:Myo5a UTSW 9 75097279 missense possibly damaging 0.67
R9293:Myo5a UTSW 9 75087312 missense probably benign 0.37
R9366:Myo5a UTSW 9 75124800 missense probably damaging 0.98
R9410:Myo5a UTSW 9 75023496 missense probably damaging 0.98
R9644:Myo5a UTSW 9 75043631 missense probably damaging 1.00
R9649:Myo5a UTSW 9 75099726 missense
R9748:Myo5a UTSW 9 75091965 missense probably damaging 0.99
R9766:Myo5a UTSW 9 75078914 missense probably damaging 0.99
X0010:Myo5a UTSW 9 75093187 missense probably damaging 1.00
Z1177:Myo5a UTSW 9 75093318 missense
Mode of Inheritance Autosomal Recessive
Local Stock Embryos
Repository

none

Last Updated 2016-05-13 3:09 PM by Stephen Lyon
Record Created unknown
Record Posted 2008-02-25
Phenotypic Description
The silver decerebrate phenotype was originally found in two ENU-induced G3 littermates. Homozygous mutants exhibit defects in both coat color and behavior, phenotypes which are always associated and therefore presumed to result from a single mutation. The fur, ears, feet and tail of homozygotes are dark gray. Several behavioral phenotypes are distinct in supine versus prone positions. When placed in a supine position, silver decerebrate mutants exhibit opisthotonus (a convulsive arching of the head and neck), abrupt movements of the feet, and have difficulty righting themselves. In the normal prone position, mutants extend all four feet caudally. In either circumstance, all of the digits are splayed.
 
Several regions of the silver decerebrate brain have been subjected to histological analysis, but the results obtained in several experiments are not consistent from one sample to another. In one analysis, holes were found in the basal ganglia, brainstem, and spinal cord, but these pathological changes were not seen in other preparations.
 
Homozygous silver decerebrate mice die at approximately three weeks of age. Due to this lethality, the strain must be maintained as a heterozygous stock. A similar spectrum of phenotypes is observed in dilute lethal and dilute opisthotonus mutants, which contain mutations in the Myo5a gene (1). No gross anatomical deficiencies of the CNS have been observed in dilute lethal mice or dilute opisthotonus (dop) rats (which carry a null allele of Myo5a) (2).
Nature of Mutation
Figure 1. Domain structure of myosin Va.  The head domain contains the actin-binding and ATP-binding sites and generates force.  A central neck domain or light-chain binding domain contains six calmodulin binding IQ motifs.  The C-terminal half of myosin Va consists of the coiled coil (CC) segments responsible for myosin heavy chain dimerization and a globular tail domain (GTD) that mediates cargo binding.  The silver decerebrate mutation results in the substitution of serine by isoleucine at amino acid 693 (red asterisk). This image is interactive. Click on the image to view other mutations found in Myo5a (red). Click on the mutations for more specific information.
The silver decerebrate mutation corresponds to a G to T transversion at position 2505 of the Myo5a transcript, in exon 17 of 41 total exons. The mutation results in the substitution of serine by isoleucine at position 693 of the encoded protein (Figure 1).
 
2489 GAGACCATCCGGATCAGCGCAGCAGGGTTTCCC
688  -E--T--I--R--I--S--A--A--G--F--P-
 
The mutated nucleotide is indicated in red lettering.
 
Please see the record for new gray for information about Myo5a.
Illustration of Mutations in
Gene & Protein
Putative Mechanism
The silver decerebrate mutation is a point mutation near the C terminal end of the head domain (aa 1-887) of myosin Va. Interestingly, other alleles of Myo5a resulting in early postnatal death are null alleles (1;3;4). It is therefore predicted that the silver decerebrate mutation probably quite fully and severely inhibits the function of myosin Va, both in skin and brain.
Primers Primers cannot be located by automatic search.
Genotyping
Silver decerebrate 1 genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
 
Primers for PCR amplification
SD1(F): 5’-ACACACTCATTACAGGATGGGCACAGT -3’
SD1(R): 5’-AGGGCCTTTCTGCTCAGAATGACAAGA -3’
 
PCR program
1) 94°C             3:00
2) 94°C             0:30
3) 60°C             0:30
4) 68°C             0:50
5) repeat steps (2-4) 35X
6) 68°C             3:00
7) 4°C              ∞
 
Primers for sequencing
SD1_seq(F): 5’- CACAGTGCTGGGCAACCCTGTCTTC -3’
SD1_seq(R): 5’- ACTGCTTGCAGAAGGCTCAGTTCCATTG -3’
 
The following sequence of 635 nucleotides (from Genbank genomic region NC_000075 for linear DNA sequence of Myo5α) is amplified:
 
92628                                                    aca cactcattac
92641 aggatgggca cagtgctggg caaccctgtc ttctttattt taaggatgtt cagtggactt
92701 cctggtaaga ctgtagtgtg tcaactggaa gggctatccc cagctcttta tttctactgc
92761 taattatctc tttgctgcta ttttatggag ttttccattt tgatcactgt tccagctttt
92821 gaatgctttg ttttctagtt tatctacttg gctcttgata aaataattta acccttgatg
92881 gcctgggtct tttgtgacct aacagttttt gtttcttcat gcagatttga tgagaagagg
92941 gcagtgcagc agctaagagc atgtggtgtc ctggagacca tccggatcag cgcagcaggg
93001 tttccctcac ggtgagccca ggcttccaat ggaactgagc cttctgcaag cagttcttga
93061 ataataagct catatgggat tcttttctag gtggacttac caagagtttt tcagccggta
93121 ccgggtccta atgaagcaaa aagatgtgct gggagataga aagcaaacgt gcaagaatgt
93181 attagagaaa ctaatattgg tgagaatggt tttcacttaa ctgtttctgg aaaggtcttg
93241 tcattctgag cagaaaggcc ct
 
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is shown in red text.
References
   1.  Searle, A. G. (1952) A lethal allele of dilute in the house mouse, Heredity 6, 395-401.
Science Writers Eva Marie Y. Moresco
Illustrators Diantha La Vine
AuthorsSophie Rutschmann, Celine Eidenschenk, Bruce Beutler
Edit History
2011-01-07 9:26 AM (current)
2010-08-27 10:09 AM
2010-08-27 10:08 AM
2010-08-10 1:54 PM
2010-08-10 1:54 PM
2010-02-03 10:32 AM