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.Peritoneal exudate cells fromSwallowmice exhibit increased rates of phagocytosis. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.
The Swallow phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R1747, some of which showed an increased rate of phagocytosis in peritoneal exudate cells (PECs; Figure 1). Phagocytosis was detected by measuring the fluorescence intensity of pHrodo® Green E. coli conjugates two hours after treatment of PECs with an experimental phagocytosis effector (e.g., Cytochalasin D). The pHrodo® Green E. coli conjugates fluoresce at acidic pH, such as in phagosomes. Some mice also exhibited hypopigmentation.
Nature of Mutation
Figure 2.Linkage mapping of the increased rate of phagocytosis using an additive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 65 mutations (X-axis) identified in the G1 male of pedigree R1747. Normalized 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 65 mutations. The increased rate of PEC phagocytosis was linked by continuous variable mapping to a mutation in Lyst: a T to C transition at base pair 13,757,422 (v38) on chromosome 13, or base pair 167,091 in the GenBank genomic region NC_000079 encoding Lyst. Linkage was found with an additive model of inheritance (P = 2.769 x 10-7), wherein 8 variant homozygotes and 8 heterozygotes departed phenotypically from 4 homozygous reference mice (Figure 2). The mutation corresponds to residue 10,815 in the mRNA sequence NM_010748.2 within exon 47 of 53 total exons.
The mutated nucleotide is indicated in red. The mutation results in a phenylalanine (F) to serine (S) substitution at position 3545 (F3545S) in the Lyst protein, and is strongly predicted by Polyphen-2 to be benign (score = 0.004).
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 Swallow mutation occurs at amino acid 3545. This image is interactive.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 2). 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 Swallow mutation is predicted to affect the first WD40 motif.
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). Defective lysosome-related functions in immune cells lead to immune deficiency, recurrent bacterial infections and lymphoproliferative disorder in CHS patients. 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 (CTL) function (14), and increased susceptibility to infections (15;16). CHS macrophages and polymorphonuclear leukocytes have normal phagocytic ability, but delayed fusion of phagosomes with lysosomes, allowing bacterial replication and escape and leading to persistent infections (2). The increased fluorescence intensity observed in the Swallow PECs indicates that phagocytosis is occuring and, similar to patients with CHS, that the fusion between the phagosomes and lysosomes may be delayed leading to protein accumulation within the phagosome.