Phenotypic Mutation 'charzard' (pdf version)
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Allelecharzard
Mutation Type nonsense
Chromosome13
Coordinate13,647,083 bp (GRCm38)
Base Change T ⇒ A (forward strand)
Gene Lyst
Gene Name lysosomal trafficking regulator
Synonym(s) D13Sfk13
Chromosomal Location 13,590,409-13,777,440 bp (+)
MGI Phenotype Strain: 1855968
Homozygous mice have a phenotype similar to human Chediak-Higashi syndrome patients, exhibiting lysosomal dysfunction with resultant protein storage; diluted coat color; abnormal melanogenesis; immune cell dysfunction resulting in increased susceptibility to bacterial, viral, and parasitic infections and decreased cytotoxic activity against tumor cells.
Accession Number

NCBI RefSeq: NM_010748.2; MGI:107448

Mapped Yes 
Amino Acid Change Cysteine changed to Stop codon
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000106188]
SMART Domains Protein: ENSMUSP00000106188
Gene: ENSMUSG00000019726
AA Change: C1347*

DomainStartEndE-ValueType
low complexity region 26 36 N/A INTRINSIC
low complexity region 72 82 N/A INTRINSIC
low complexity region 399 412 N/A INTRINSIC
low complexity region 1333 1344 N/A INTRINSIC
low complexity region 2295 2307 N/A INTRINSIC
low complexity region 2427 2445 N/A INTRINSIC
low complexity region 2534 2546 N/A INTRINSIC
Pfam:PH_BEACH 3006 3101 5.8e-25 PFAM
Beach 3118 3408 1.25e-193 SMART
Blast:Beach 3441 3478 9e-13 BLAST
WD40 3539 3579 5.75e-1 SMART
WD40 3591 3630 2.89e-5 SMART
WD40 3633 3676 1.38e0 SMART
WD40 3724 3765 1.27e-1 SMART
Predicted Effect probably null
Phenotypic Category pigmentation, skin/coat/nails
Penetrance  
Alleles Listed at MGI

All Mutations and Alleles(57) : Chemically induced (ENU)(9) Gene trapped(34) Radiation induced(1) Spontaneous(9) Targeted(4)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00156:Lyst APN 13 13648878 missense probably benign 0.00
IGL00474:Lyst APN 13 13643536 missense possibly damaging 0.62
IGL00484:Lyst APN 13 13709603 missense probably benign 0.02
IGL00492:Lyst APN 13 13678175 missense possibly damaging 0.54
IGL00807:Lyst APN 13 13650423 missense possibly damaging 0.91
IGL00949:Lyst APN 13 13635485 missense possibly damaging 0.89
IGL00952:Lyst APN 13 13678107 missense probably benign 0.05
IGL01305:Lyst APN 13 13678056 missense probably benign 0.01
IGL01317:Lyst APN 13 13670870 missense probably benign 0.00
IGL01419:Lyst APN 13 13635838 missense probably benign 0.00
IGL01445:Lyst APN 13 13651714 missense probably benign 0.00
IGL01690:Lyst APN 13 13743246 missense probably damaging 1.00
IGL01791:Lyst APN 13 13635302 missense probably damaging 1.00
IGL01809:Lyst APN 13 13637803 missense probably damaging 1.00
IGL01896:Lyst APN 13 13635577 missense probably benign 0.04
IGL01938:Lyst APN 13 13637424 missense possibly damaging 0.93
IGL01986:Lyst APN 13 13775627 critical splice donor site probably null 0.00
IGL02022:Lyst APN 13 13664044 nonsense probably null 0.00
IGL02044:Lyst APN 13 13712846 missense probably damaging 1.00
IGL02157:Lyst APN 13 13660956 missense probably benign 0.00
IGL02185:Lyst APN 13 13661093 nonsense probably null 0.00
IGL02215:Lyst APN 13 13660956 missense probably benign 0.00
IGL02245:Lyst APN 13 13660956 missense probably benign 0.00
IGL02246:Lyst APN 13 13660956 missense probably benign 0.00
IGL02247:Lyst APN 13 13660956 missense probably benign 0.00
IGL02297:Lyst APN 13 13638092 nonsense probably null 0.00
IGL02411:Lyst APN 13 13660956 missense probably benign 0.00
IGL02415:Lyst APN 13 13660956 missense probably benign 0.00
IGL02419:Lyst APN 13 13660956 missense probably benign 0.00
IGL02420:Lyst APN 13 13660956 missense probably benign 0.00
IGL02429:Lyst APN 13 13660956 missense probably benign 0.00
IGL02501:Lyst APN 13 13711645 missense probably benign 0.02
IGL02522:Lyst APN 13 13634705 missense possibly damaging 0.81
IGL02535:Lyst APN 13 13650342 missense probably benign 0.00
IGL02596:Lyst APN 13 13660956 missense probably benign 0.00
IGL02601:Lyst APN 13 13660956 missense probably benign 0.00
IGL02603:Lyst APN 13 13660956 missense probably benign 0.00
IGL02608:Lyst APN 13 13712754 missense probably damaging 0.98
IGL02622:Lyst APN 13 13681390 missense probably damaging 1.00
IGL02690:Lyst APN 13 13641125 missense possibly damaging 0.58
IGL02715:Lyst APN 13 13674320 splice site 0.00
IGL02725:Lyst APN 13 13760827 missense probably damaging 1.00
IGL02729:Lyst APN 13 13674339 missense possibly damaging 0.81
IGL02729:Lyst APN 13 13746609 missense possibly damaging 0.95
IGL02820:Lyst APN 13 13638058 missense probably benign 0.02
IGL02945:Lyst APN 13 13761198 missense probably benign 0.38
IGL02981:Lyst APN 13 13634911 missense possibly damaging 0.84
IGL03087:Lyst APN 13 13635056 missense unknown 0.00
IGL03149:Lyst APN 13 13681444 missense probably damaging 0.98
IGL03158:Lyst APN 13 13651752 splice site 0.00
IGL03226:Lyst APN 13 13709559 missense probably damaging 1.00
IGL03242:Lyst APN 13 13656881 nonsense probably null 0.00
IGL03385:Lyst APN 13 13656980 nonsense probably null 0.00
50-cal UTSW 13 13708212 critical splice donor site probably null
charlotte_gray UTSW 13 13602026 nonsense
grey_wolf UTSW 13 unclassified
lightspeed UTSW 13 13740536 missense possibly damaging 0.91
robin UTSW 13 13648802 nonsense probably null
sooty UTSW 13 unclassified
souris UTSW 13 13683224 critical splice donor site
Swallow UTSW 13 13757422 missense probably benign 0.00
vulpix UTSW 13 13696794 splice donor site probably null
ANU22:Lyst UTSW 13 13678056 missense probably benign 0.01
IGL02835:Lyst UTSW 13 13661100 missense possibly damaging 0.82
P0031:Lyst UTSW 13 13664031 missense probably damaging 1.00
R0012:Lyst UTSW 13 13687694 missense probably benign 0.10
R0012:Lyst UTSW 13 13687694 missense probably benign 0.10
R0031:Lyst UTSW 13 13708156 missense probably benign 0.14
R0115:Lyst UTSW 13 13677952 missense probably benign 0.00
R0212:Lyst UTSW 13 13635985 missense possibly damaging 0.93
R0386:Lyst UTSW 13 13708214 splice donor site probably benign
R0393:Lyst UTSW 13 13647079 missense probably benign 0.01
R0415:Lyst UTSW 13 13711610 splice acceptor site probably benign
R0446:Lyst UTSW 13 13638048 missense probably benign 0.00
R0481:Lyst UTSW 13 13677952 missense probably benign 0.00
R0499:Lyst UTSW 13 13616713 missense probably damaging 1.00
R0506:Lyst UTSW 13 13638015 missense probably benign 0.00
R0530:Lyst UTSW 13 13757306 splice acceptor site probably benign
R0541:Lyst UTSW 13 13681293 missense probably benign 0.00
R0570:Lyst UTSW 13 13709386 missense probably benign 0.26
R0680:Lyst UTSW 13 13650341 missense probably benign 0.01
R0842:Lyst UTSW 13 13678241 nonsense probably null
R0848:Lyst UTSW 13 13634930 missense probably benign 0.00
R1014:Lyst UTSW 13 13634060 missense possibly damaging 0.49
R1205:Lyst UTSW 13 13680202 missense probably benign 0.00
R1251:Lyst UTSW 13 13634483 missense probably benign 0.00
R1304:Lyst UTSW 13 13751984 nonsense probably null
R1445:Lyst UTSW 13 13640054 missense possibly damaging 0.94
R1475:Lyst UTSW 13 13708212 critical splice donor site probably null
R1479:Lyst UTSW 13 13634482 missense probably benign 0.00
R1484:Lyst UTSW 13 13678190 missense probably benign 0.01
R1498:Lyst UTSW 13 13650375 missense possibly damaging 0.49
R1540:Lyst UTSW 13 13635101 missense possibly damaging 0.81
R1611:Lyst UTSW 13 13634897 missense probably damaging 0.97
R1653:Lyst UTSW 13 13635226 missense probably damaging 1.00
R1669:Lyst UTSW 13 13644087 missense possibly damaging 0.90
R1686:Lyst UTSW 13 13634705 missense possibly damaging 0.81
R1694:Lyst UTSW 13 13661161 missense probably damaging 0.98
R1709:Lyst UTSW 13 13707616 splice acceptor site probably benign
R1747:Lyst UTSW 13 13757422 missense probably benign 0.00
R1793:Lyst UTSW 13 13647083 nonsense probably null
R1871:Lyst UTSW 13 13651712 missense probably benign 0.00
R1905:Lyst UTSW 13 13634134 missense probably benign 0.00
R1958:Lyst UTSW 13 13616618 missense probably damaging 1.00
R1969:Lyst UTSW 13 13730344 missense probably damaging 0.99
R2040:Lyst UTSW 13 13641222 missense probably benign 0.00
R2109:Lyst UTSW 13 13712820 missense possibly damaging 0.46
R2116:Lyst UTSW 13 13635701 missense probably damaging 0.99
R2121:Lyst UTSW 13 13660971 missense probably damaging 1.00
R2127:Lyst UTSW 13 13635262 missense probably damaging 1.00
R2187:Lyst UTSW 13 13709341 missense possibly damaging 0.61
R2238:Lyst UTSW 13 13743263 missense probably benign 0.41
R2258:Lyst UTSW 13 13637658 missense probably benign 0.00
R2292:Lyst UTSW 13 13740495 missense probably damaging 1.00
R2368:Lyst UTSW 13 13696663 missense probably damaging 0.96
R2908:Lyst UTSW 13 13669873 missense probably benign 0.03
R3001:Lyst UTSW 13 13696705 missense probably benign
R3002:Lyst UTSW 13 13696705 missense probably benign
R3024:Lyst UTSW 13 13658687 missense probably benign
R3113:Lyst UTSW 13 13669927 missense probably benign 0.12
R3406:Lyst UTSW 13 13635230 missense possibly damaging 0.56
R3972:Lyst UTSW 13 13706625 missense possibly damaging 0.67
R3978:Lyst UTSW 13 13634168 missense possibly damaging 0.82
R4032:Lyst UTSW 13 13616665 missense probably damaging 1.00
R4192:Lyst UTSW 13 13740513 missense probably damaging 1.00
R4206:Lyst UTSW 13 13635989 missense probably benign 0.03
R4298:Lyst UTSW 13 13634887 missense probably damaging 1.00
R4344:Lyst UTSW 13 13698466 missense probably benign 0.06
R4441:Lyst UTSW 13 13635383 missense probably damaging 1.00
R4445:Lyst UTSW 13 13709564 missense probably benign 0.42
R4477:Lyst UTSW 13 13635383 missense probably damaging 1.00
R4493:Lyst UTSW 13 13635383 missense probably damaging 1.00
R4494:Lyst UTSW 13 13635383 missense probably damaging 1.00
R4495:Lyst UTSW 13 13635383 missense probably damaging 1.00
R4622:Lyst UTSW 13 13674398 missense probably benign 0.01
R4638:Lyst UTSW 13 13696794 unclassified probably null
R4658:Lyst UTSW 13 13635383 missense probably damaging 1.00
R4675:Lyst UTSW 13 13635383 missense probably damaging 1.00
R4719:Lyst UTSW 13 13650350 missense probably benign
R4729:Lyst UTSW 13 13637901 missense probably damaging 1.00
R4774:Lyst UTSW 13 13740597 missense probably damaging 1.00
R4811:Lyst UTSW 13 13777100 missense probably benign 0.33
R4877:Lyst UTSW 13 13683149 missense probably damaging 1.00
R4920:Lyst UTSW 13 13647060 missense possibly damaging 0.79
R4933:Lyst UTSW 13 13637764 missense probably damaging 0.98
R4933:Lyst UTSW 13 13759378 unclassified probably benign 0.12
R4958:Lyst UTSW 13 13635463 missense probably benign 0.00
R4982:Lyst UTSW 13 13725954 missense probably damaging 1.00
R4992:Lyst UTSW 13 13661163 missense probably damaging 1.00
R5024:Lyst UTSW 13 13634404 missense probably benign
R5049:Lyst UTSW 13 13636064 missense probably damaging 1.00
R5079:Lyst UTSW 13 13757353 missense probably benign 0.08
R5254:Lyst UTSW 13 13683070 missense probably benign 0.00
R5266:Lyst UTSW 13 13660970 missense probably damaging 1.00
R5279:Lyst UTSW 13 13648802 nonsense probably null
R5285:Lyst UTSW 13 13634426 missense probably benign 0.01
R5364:Lyst UTSW 13 13656854 missense probably benign 0.35
R5435:Lyst UTSW 13 13777064 missense possibly damaging 0.64
R5516:Lyst UTSW 13 13644122 missense probably benign 0.10
R5524:Lyst UTSW 13 13746779 missense probably benign 0.03
R5591:Lyst UTSW 13 13743333 missense probably damaging 0.99
R5592:Lyst UTSW 13 13743333 missense probably damaging 0.99
R5593:Lyst UTSW 13 13743333 missense probably damaging 0.99
R5594:Lyst UTSW 13 13743333 missense probably damaging 0.99
R5594:Lyst UTSW 13 13759397 missense probably benign 0.00
R5644:Lyst UTSW 13 13637496 missense possibly damaging 0.58
R5659:Lyst UTSW 13 13634627 missense possibly damaging 0.58
R5908:Lyst UTSW 13 13696761 nonsense probably null
R5969:Lyst UTSW 13 13687813 unclassified probably null
X0024:Lyst UTSW 13 13634448 missense probably benign 0.00
X0026:Lyst UTSW 13 13683043 splice acceptor site probably benign
X0026:Lyst UTSW 13 13751970 missense probably damaging 0.99
X0060:Lyst UTSW 13 13650317 splice acceptor site probably benign
Z1088:Lyst UTSW 13 13743433 missense probably benign 0.09
Mode of Inheritance Autosomal Recessive
Local Stock
Repository
Last Updated 05/24/2017 10:37 AM by Katherine Timer
Record Created 12/03/2014 7:42 AM by Carlos Reyna
Record Posted 06/02/2016
Phenotypic Description
Figure 1. Charzard mice (right) exhibit hypopigmentation of the fur. A wild-type littermate (left) is shown for reference.

The charzard phenotype was identified among G3 mice of the pedigree R1793, some of which exhibited hypopigmentation of the fur (Figure 1).

Nature of Mutation

Whole exome HiSeq sequencing of the G1 grandsire identified 123 mutations. Among these, only one affected a gene with known effects on fur pigmentation: Lyst. The mutation in Lyst was presumed to be causative because the charzard hypopigmentation phenotype mimics other known alleles of Lyst (see MGI for a list of Lyst alleles as well as the entry for souris). The Lyst mutation is a T to C transition at base pair 13,647,083 (v38) on chromosome 13, or base pair 56,745 in the GenBank genomic region NC_000079 for the Lyst gene. The mutation corresponds to residue 4,222 in the mRNA sequence NM_010748 within exon 11 of 53 total exons.

 

4205 ATGAGCTCAAGAACGTGTTCAGAAGACTTAACT

1342 -M--S--S--R--T--C--S--E--D--L--T-

 

The mutated nucleotide is indicated in red.  The mutation results in substitution of cysteine (C) 1,347 to a premature stop codon (C1347*) in the Lyst protein.

Protein Prediction

Figure 1. Domain structure of the Lyst protein. The Lyst protein is a 3788-amino acid protein whose biochemical functions remain unknown. The N-terminal portion of the protein contains approximately twenty repeats with homology to ARM and HEAT repeat motifs and a perilipin domain (PD). The C-terminal portion of Lyst contains a BEACH domain and seven WD40 motifs. The charzard mutation results in substitution of cysteine (C) 1,347 to a premature stop codon (C1347*). This image is interactive. Click on the image to view other mutations found in Lyst (red). Click on the mutations for more specific information. There are two additional alleles in the Lyst gene: sooty and grey wolf. The locations of their mutations is unknown.

The Lyst gene encodes the protein Lyst (also CHS/Beige), a 3788-amino acid protein whose biochemical functions remain unknown (Figure 2). A large N-terminal portion of the protein (amino acids 1-3,132) contains approximately twenty repeats with homology to ARM (Armadillo) and HEAT (huntingtin, elongation factor 3, A subunit of protein phosphatase A, target of rapamycin) repeat motifs (1;2). ARM and HEAT motifs are α-helical domains of about 50 amino acids that pack together to form elongated “solenoids” (3); evidence suggests they mediate protein associations at the membrane (4), and vesicle transport (5), respectively. A perilipin domain (PD; amino acids 1079-1313) may interact with lipids. The C-terminus of Lyst contains two distinct domains, a BEACH (beige and chediak) domain (amino acids 3132-3472) and seven WD40 motifs (1). The BEACH domain is a 345-amino acid region of unknown function (1), and WD40 motifs are protein interaction motifs that typically form β sheets arranged in a 7-bladed β propeller fold (6). The charzard mutation results in substitution of cysteine (C) 1,347 to a premature stop codon (C1347*). Amino acid 1,347 is within the ARM/HEAT domain, C-terminal to the perilipin domain.

 

Please see the record for souris for information about Lyst.

Putative Mechanism

In humans, mutations in the LYST gene cause Chediak-Higashi Syndrome (CHS, OMIM #214500), a rare autosomal recessive disorder characterized by oculocutaneous albinism, severe immune deficiency, bleeding tendency, recurrent pyogenic infection, progressive neurologic defects and a lymphoproliferative syndrome [(7;8); reviewed in (2)]. These defects are caused by the aberrant formation of giant granules within a variety of cell types, and disrupted intracellular protein trafficking (2;9;10). The enlarged granules consist of organelles such as lysosomes, melanosomes, cytolytic granules and platelet dense bodies, and it is thought that the increased size of these organelles inhibits their migration and fusion at the cell surface and/or organelle-organelle fusion. There is no clear understanding of the molecular mechanisms of Lyst protein function, or how its loss leads to the formation of enlarged lysosomes and lysosome-related organelles.

 

In mice, mutations in Lyst cause the beige phenotype (7;8). As in humans, beige mice exhibit hypopigmentation, bleeding tendency, and defective immune cell function resulting from the formation of giant granules in melanosomes, lymphocytes, neutrophils, and other cell types (10-12). Beige mice have defective NK cell (13) and cytotoxic T lymphocyte function (14), and increased susceptibility to infections including MCMV (15;16). However, beige mice do not develop lymphoproliferative disorder, even after challenge with infection (15). The charzard hypopigmentation phenotype mimics other known alleles of Lyst indicating that there is loss of function in the Lystcharzard protein. Immune cell phenotypes were not observed in charazard.

Primers PCR Primer
charzard(F):5'- CGTCTGTCACTTAAGTTCCATGTAAG -3'
charzard(R):5'- CAAACATAAAACATGGTACTGGGC -3'

Sequencing Primer
charzard_seq(F):5'- GTAGTTATAACCTGAACAATTGCCG -3'
charzard_seq(R):5'- ATAAAACATGGTACTGGGCTAAATAG -3'
References

1. Nagle, D. L., Karim, M. A., Woolf, E. A., Holmgren, L., Bork, P., Misumi, D. J., McGrail, S. H., Dussault, B. J.,Jr, Perou, C. M., Boissy, R. E., Duyk, G. M., Spritz, R. A., and Moore, K. J. (1996) Identification and Mutation Analysis of the Complete Gene for Chediak-Higashi Syndrome. Nat Genet. 14, 307-311.

  2. Shiflett, S. L., Kaplan, J., and Ward, D. M. (2002) Chediak-Higashi Syndrome: A Rare Disorder of Lysosomes and Lysosome Related Organelles. Pigment Cell Res. 15, 251-257.

  3. Andrade, M. A., Petosa, C., O'Donoghue, S. I., Muller, C. W., and Bork, P. (2001) Comparison of ARM and HEAT Protein Repeats. J Mol Biol. 309, 1-18.

  4. Peifer, M., Berg, S., and Reynolds, A. B. (1994) A Repeating Amino Acid Motif Shared by Proteins with Diverse Cellular Roles. Cell. 76, 789-791.

  5. Andrade, M. A., and Bork, P. (1995) HEAT Repeats in the Huntington's Disease Protein. Nat Genet. 11, 115-116.

  6. Sondek, J., Bohm, A., Lambright, D. G., Hamm, H. E., and Sigler, P. B. (1996) Crystal Structure of a G-Protein Beta Gamma Dimer at 2.1A Resolution. Nature. 379, 369-374.

  7. Barbosa, M. D., Nguyen, Q. A., Tchernev, V. T., Ashley, J. A., Detter, J. C., Blaydes, S. M., Brandt, S. J., Chotai, D., Hodgman, C., Solari, R. C., Lovett, M., and Kingsmore, S. F. (1996) Identification of the Homologous Beige and Chediak-Higashi Syndrome Genes. Nature. 382, 262-265.

  8. Perou, C. M., Moore, K. J., Nagle, D. L., Misumi, D. J., Woolf, E. A., McGrail, S. H., Holmgren, L., Brody, T. H., Dussault, B. J.,Jr., Monroe, C. A., Duyk, G. M., Pryor, R. J., Li, L., Justice, M. J., and Kaplan, J. (1996) Identification of the Murine Beige Gene by YAC Complementation and Positional Cloning. Nat Genet. 13, 303-308.

  9. Faigle, W., Raposo, G., Tenza, D., Pinet, V., Vogt, A. B., Kropshofer, H., Fischer, A., de Saint-Basile, G., and Amigorena, S. (1998) Deficient Peptide Loading and MHC Class II Endosomal Sorting in a Human Genetic Immunodeficiency Disease: The Chediak-Higashi Syndrome. J Cell Biol. 141, 1121-1134.

  10. Burkhardt, J. K., Wiebel, F. A., Hester, S., and Argon, Y. (1993) The Giant Organelles in Beige and Chediak-Higashi Fibroblasts are Derived from Late Endosomes and Mature Lysosomes. J Exp Med. 178, 1845-1856.

  11. Kelly, E. M. (1957) Beige, Bg. Mouse News Lett. 16, 36-36.

  12. Lutzner, M. A., Lowrie, C. T., and Jordan, H. W. (1967) Giant Granules in Leukocytes of the Beige Mouse. J Hered. 58, 299-300.

  13. Roder, J. C. (1979) The Beige Mutation in the Mouse. I. A Stem Cell Predetermined Impairment in Natural Killer Cell Function. J Immunol. 123, 2168-2173.

  14. Saxena, R. K., Saxena, Q. B., and Adler, W. H. (1982) Defective T-Cell Response in Beige Mutant Mice. Nature. 295, 240-241.

  15. Shellam, G. R., Allan, J. E., Papadimitriou, J. M., and Bancroft, G. J. (1981) Increased Susceptibility to Cytomegalovirus Infection in Beige Mutant Mice 3. Proc Natl Acad Sci U S A. 78, 5104-5108.

  16. Kirkpatrick, C. E., and Farrell, J. P. (1982) Leishmaniasis in Beige Mice. Infect Immun. 38, 1208-1216.

Science Writers Anne Murray
Illustrators Katherine Timer
AuthorsCarlos Reyna, Jamie Russell, and Bruce Beutler
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