FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein that regulates intracellular protein trafficking in endosomes, and may be involved in pigmentation. Mutations in this gene are associated with Chediak-Higashi syndrome, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants, though the full-length nature of some of these variants has not been determined. [provided by RefSeq, Apr 2013] PHENOTYPE: 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. [provided by MGI curators]
Figure 1. The charcoal mice (top) exhibit hypopigmentation of the fur. A wild-type (C57BL/6J) littermate is shown (bottom) for comparison.
The charcoal phenotype was identified among G3 mice of the pedigree R5908, some of which exhibited hypopigmentation of the fur (Figure 1).
Nature of Mutation
Figure 2.Linkage mapping of the pigmentation phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 62 mutations (X-axis) identified in the G1 male of pedigree R5908. Binary 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 62 mutations. The hypopigmentation phenotype was linked to three mutations on chromosome 13: Lyst, Pom121l2, and Prl81. The mutation in Lyst was presumed to be causative because the charcoal 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 A transversion at base pair 13,696,761 (v38) on chromosome 13, or base pair 106,422 in the GenBank genomic region NC_000079 for the Lyst gene. The strongest association was found with a recessive model of inheritance to the pigmentation phenotype (P = 0.001030), wherein four affected mice were homozygous for the variant allele, and 12 unaffected mice were either heterozygous (N = 6) or homozygous for the reference allele (N = 6) (Figure 2).
The mutation corresponds to residue 8,263 in the mRNA sequence NM_010748 within exon 30 of 53 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of tyrosine 2,694 for a premature stop codon (Y2694*) in the Lyst protein.
Figure 3. 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 charcoal mutation is shown. This image is interactive. Click on the mutations (red) for more specific information.
The Lyst gene encodes the protein Lyst (also CHS/Beige), a 3788-amino acid protein whose biochemical functions remain unknown (Figure 3). A large N-terminal portion of the protein (amino acids 1-3132) 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. 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 charcoal mutation results in substitution of tyrosine 2,694 for a premature stop codon (Y2694*); Tyr2694 is within the ARM/HEAT domain.
Please see the record for souris for information about Lyst.
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 charcoal hypopigmentation phenotype mimics other known alleles of Lyst (see MGI for a list of Lyst alleles as well as the Beutler alleles souris and charlotte_gray) indicating that there is loss of function in the Lystcharcoal protein.
charcoal(F):5'- AGTGTTACTTATCCCACCTCTTGAG -3'
charcoal(R):5'- TTTTGTAACAGGTTAGCCAAGC -3'
charcoal_seq(F):5'- ACCTCTTGAGTATTTTCACCAACATC -3'
charcoal_seq(R):5'- TGAGTTCAAAGTCAACCTAGGC -3'