Alternative titles; symbols
HGNC Approved Gene Symbol: LYST
Cytogenetic location: 1q42.3 Genomic coordinates (GRCh38): 1:235,661,031-235,883,713 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q42.3 | Chediak-Higashi syndrome | 214500 | Autosomal recessive | 3 |
Studies of the Chediak-Higashi syndrome (CHS; 214500) led to identification and characterization of the LYST gene. In 'beige' mice, the murine equivalent of Chediak-Higashi syndrome, Perou et al. (1996) succeeded in identifying the 'beige' gene by in vitro complementation and positional cloning, and confirmed its identification by defining mutations in 2 independent mutant alleles. The sequence of the 'beige' gene transcript showed strong nucleotide homology to multiple human ESTs, one or more of which may be associated with the gene that is mutant in Chediak-Higashi syndrome. The predicted 2,186-amino acid polypeptide shows significant amino acid homology to orphan proteins identified in Saccharomyces cerevisiae (e.g., CDC4), Caenorhabditis elegans, and humans (e.g., CDC4L).
Although Perou et al. (1996) and Barbosa et al. (1996) reported identification of the 'beige' gene, the 2 cDNAs were quite different. Nagle et al. (1996) described the sequence of a human cDNA homologous to mouse 'beige,' identified pathologic mutations in patients with Chediak-Higashi syndrome, and clarified the discrepancies of the previous reports of sequence. Analysis of the CHS1 polypeptide demonstrated that its modular architecture is similar to that of the yeast vacuolar sorting protein VPS15. Nagle et al. (1996) screened human cDNA libraries with mouse 'beige' probes to yield the human 'beige' cDNA homolog, and found 87.9% amino acid identity between the 2 sequences. The predicted human protein comprises 3,801 amino acids, with a molecular mass of approximately 43 kD. Barbosa et al. (1997) reported the sequences of 2 major mRNA isoforms of the CHS1 gene in human and mouse. These isoforms differ both in size and in sequence at the 3-prime end of their coding domains, with a small isoform (approximately 5.8 kb) arising from incomplete splicing and reading through an intron. These mRNAs also differ in tissue distribution of transcription and in predicted biologic properties.
Kunieda et al. (2000) cloned the bovine LYST gene and found 90.4% amino acid sequence identity with the human sequence and 83.2% identity with the mouse sequence.
Jackson (1997) reviewed homologous pigmentation mutations in human, mouse, and other model organisms. He tabulated the available data on all pigmentation genes cloned from mouse or human, and focused on 3 particular systems. One family of genes, including LYST and HPS (203300), shows the relationship between melanosomes and lysosomes. The G protein-coupled receptor, endothelin receptor-B (EDNRB; 131244) and its ligand, endothelin-3 (EDN3; 131242) are required for the development of both melanocytes and enteric neurons; mutations in either result in the combination of megacolon and pigmentary anomaly (spotting). The melanocortin-1 receptor (MC1R; 155555) is expressed only in melanocytes, but mutations that cause overexpression of agouti protein (ASIP; 600201), an antagonist of the receptor, result in obesity in transgenic mice, thus highlighting a role of melanocortins in weight homeostasis.
In cells from patients with the Chediak-Higashi syndrome, Faigle et al. (1998) found that peptide loading onto major histocompatibility complex class II molecules and antigen presentation were strongly delayed. Results of other studies suggested that the product of the CHS1 gene is required for sorting endosomal resident proteins into late multivesicular endosomes by a mechanism involving microtubules.
By combining genetic perturbation of sphingolipid metabolism with quantification of TLR (see 601194) signaling steps and mass spectrometry-based lipidomics in mouse cells, Koberlin et al. (2015) uncovered a circular network of coregulated sphingolipids and glycerophospholipids. Quantitative lipidomics on fibroblasts from patients with mutations in GBA (606463), GALC (606890), ASAH1 (613468), or LYST revealed conservation of the circular organization of lipid coregulation across species, cell types, and genetic perturbations. The functional annotation accurately predicted TLR-mediated inflammatory responses, in terms of changes in lipid abundance and lipid species, in patient cells.
Karim et al. (2002) found that the LYST gene consists of 55 exons, with 2 alternative, mutually exclusive 5-prime untranslated regions, whose sequences appear to be encoded by a complex pattern of alternative promoters and alternative RNA splicing.
Because of the relation of the LYST gene to Chediak-Higashi syndrome, linkage studies of the disorder led to the mapping of the gene. Jenkins et al. (1991) predicted that the CHS gene may reside in distal 1q because in the mouse the homologous condition to Chediak-Higashi syndrome shows linkage to the nidogen gene (131390) which is located on human 1q. Barrat et al. (1996) mapped the CHS locus by linkage analysis to a 5-cM interval on chromosome 1q42.1-q42.2. The highest lod score (5.38 at theta = 0) was obtained with the marker D1S235. They used haplotype analysis to define D1S2680 as the telomeric flanking marker and D1S163 as the centromeric flanking marker. Barrat et al. (1996) identified 3 YAC clones which covered the entire region in a contig.
Kunieda et al. (2000) showed that the bovine LYST gene is on chromosome 28 using a bovine/murine somatic cell hybrid panel.
Barbosa et al. (1997) identified novel mutations within the region of the coding domain common to both LYST isoforms in 3 CHS patients: C-to-T transitions that generated stop codons (R50X; 606897.0006 and Q1029X; 606897.0007) were found in 2 patients, and a novel frameshift mutation (deletion of nucleotides 3073 and 3074 of the coding domain) was found in a third. Northern blots of lymphoblastoid mRNA from CHS patients revealed loss of the largest transcript (approximately 13.5 kb) in 2 of 7 CHS patients, while the small mRNA was undiminished in abundance. These results suggested that the small isoform alone cannot complement Chediak-Higashi syndrome. All beige and CHS1 mutations that had been identified were predicted to result in either truncated or absent proteins.
Karim et al. (1997) reported 2 homozygous LYST mutations. One of these, a frameshift at codon 3197 (606897.0005), supported their assertion that the functional LYST protein is a predicted 3,801-amino acid polypeptide encoded by a 13.5-kb mRNA.
Runkel et al. (2006) reported the mouse grey mutation, which was generated in an N-ethyl-N-nitrosourea mutation screen. Affected mice segregated a seizure phenotype and grey coat color. Melanosomes of melanocytes associated with hair follicles, the choroid layer of the eye, and neural tube-derived pigment epithelium of the retina were larger and irregularly shaped in affected mice compared with wildtype controls. Secretory vesicles in dermal mast cells of mutant skin were also enlarged. Runkel et al. (2006) found that the grey phenotype was caused by a point mutation in the splice donor site of exon 25 in the Lyst gene, leading to a missense mutation and the loss of 77 amino acids encoded by exon 25. The C-terminal end of the protein was intact. Western blot analysis showed that the grey mutation caused instability of the Lyst protein.
Nagle et al. (1996) identified homozygosity for a single-base deletion within codon 489 of the LYST gene in a boy with the typical childhood form of Chediak-Higashi syndrome (214500). The deletion resulted in a frameshift and premature translational termination at codon 566.
In an adult male with late-onset Chediak-Higashi syndrome (214500), Nagle et al. (1996) found homozygosity for a C-to-T transition in codon 1103, CGA to TGA, resulting in a nonsense mutation.
In a 1-year-old girl with typical childhood CHS (214500) manifested by 'partial' oculocutaneous albinism, photophobia, and cytoplasmic inclusions in her white blood cells, Nagle et al. (1996) found a frameshift mutation, a single-base duplication in codon 40, GCA to GGCA. The same mutation had previously been identified by Barbosa et al. (1996). Nagle et al. (1996) had not yet identified the second mutation in this patient who was presumably a compound heterozygote.
In an offspring of first-cousin parents, the proband in 1 of the families used by Fukai et al. (1996) for mapping the gene, Karim et al. (1997) found homozygosity by descent for a 1-bp insertion (adenine) at codons lys633/lys634 (in a cluster of 6 adenine residues). The insertion resulted in a frameshift and premature translational termination at codon 638. The parents were heterozygous for the mutation. The patient was a Kuwaiti Bedouin boy with typical severe childhood CHS (214500), with silvery hair and oculocutaneous albinism, recurrent pyogenic infections, cervical lymphadenopathy, hepatosplenomegaly, neutropenia, mild thrombocytopenia, and low serum IgG. Typical cytoplasmic giant granules were seen in peripheral blood leukocytes, and a skin biopsy showed large irregular melanin granules in the melanocytes.
Karim et al. (1997) found a frameshift mutation in the LYST gene in a Turkish boy with typical severe childhood CHS (214500). His parents were first cousins. He was homozygous for a single base deletion (adenine) within codon tyr3197 (TAT), resulting in a frameshift and translational termination at codon 3258.
In a patient with CHS (214500) who was a compound heterozygote (patient 373), Barbosa et al. (1997) found a C-to-T substitution at nucleotide 148 of the coding domain of the LYST gene. The substitution created a stop codon at amino acid 50 (R50X). The mutation occurred within a CpG dinucleotide.
In a CHS (214500) patient, Barbosa et al. (1997) found homozygosity for a C-to-T substitution at nucleotide 3085 of the coding domain that created a stop codon at amino acid 1029 (Q1029X).
In a 6-year-old male with Chediak-Higashi syndrome (214500), in whom maternal uniparental isodisomy was found, Dufourcq-Lagelouse et al. (1999) used a protein truncated test to analyze the LYST gene and identify in the proband a shorter protein than the one observed in controls in an in vitro translation assay of a PCR fragment. Direct sequencing in this fragment revealed a homozygous T deletion between nucleotides 2620-2623, leading to a termination codon at amino acid position 898. The mother was found to be heterozygous for this mutation, but no mutation was detected in the father's DNA. The diagnosis of CHS was made in this patient at the age of 5.5 years when he developed features characteristic of an accelerated phase of the disease. These included fever, edema, hepatosplenomegaly, lymphadenopathy, pancytopenia, coagulation disorder, and infiltration of most organs by lymphocytes and histiocytes. In addition, the patient presented with partial oculocutaneous albinism, and giant granulations were detected in his leukocytes. Postnatal physical and mental development had been totally normal. The child died at 6 years of age from veino-occlusive disease following an attempt at bone marrow transplantation.
In a Japanese patient from consanguineous parents and the adult type of CHS (214500), Karim et al. (2002) found homozygosity for a 4688G-A transition in the LYST gene, resulting in an arg1563-to-his (R1563H) missense mutation.
In a Japanese patient with consanguineous parents and the adult type of CHS (214500), Karim et al. (2002) found homozygosity for a 5996T-A transversion in the LYST gene, resulting in a val1999-to-asp (V1999D) missense mutation.
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Runkel, F., Bussow, H., Seburn, K. L., Cox, G. A., Ward, D. M., Kaplan, J., Franz, T. Grey, a novel mutation in the murine Lyst gene, causes the beige phenotype by skipping of exon 25. Mammalian Genome 17: 203-210, 2006. [PubMed: 16518687] [Full Text: https://doi.org/10.1007/s00335-005-0015-1]