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LYST
lysosomal trafficking regulator
The LYST gene provides instructions for making the lysosomal trafficking regulator protein, crucial for the normal function and regulation of lysosomes within cells. The LYST gene is responsible for producing a protein involved in the transport and regulation of materials within cellular lysosomes.
LYST is located on the long (q) arm of chromosome 1, at band 1q42.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The LYST gene, also known as CHS1, encodes the lysosomal trafficking regulator protein. This protein is believed to play a significant role in the movement and processing of substances within lysosomes, which are critical cellular organelles. Lysosomes are essential for waste breakdown, defence against bacteria, and recycling of cellular components. Understanding the LYST gene's function is important for comprehending conditions that arise when its activity is disrupted.
What the gene does
The lysosomal trafficking regulator protein, produced from the LYST gene, is thought to be involved in the transport of various materials into lysosomes. Lysosomes function as the cell's primary recycling and waste disposal units, utilising digestive enzymes to break down toxic substances, degrade invading bacteria, and process worn-out cellular parts. While the precise molecular mechanism remains under investigation, research indicates that the LYST protein influences the size of lysosomes and helps regulate their movement throughout the cell. Impaired function of this protein can disrupt the normal activity of these vital organelles, leading to cellular dysfunction.
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Chromosome location
The LYST gene is located on the long arm (q) of chromosome 1, specifically at position 1q42.3. This chromosomal location indicates its physical address within the human genome. The gene spans a significant region of DNA, containing the genetic code for the large lysosomal trafficking regulator protein.
Protein structure
The LYST protein is a large protein consisting of 3801 amino acids with several distinct domains. It includes multiple disordered regions, found at amino acids 148-173, 1181-1203, 1221-1256, and 2205-2224. The protein also features several WD repeats: WD 1 (amino acids 662-700), WD 2 (amino acids 1582-1626), WD 3 (amino acids 3563-3602), WD 4 (amino acids 3614-3653), WD 5 (amino acids 3656-3699), WD 6 (amino acids 3700-3744), and WD 7 (amino acids 3749-3788). Additionally, it contains a BEACH-type PH domain (amino acids 3009-3115) and a BEACH domain (amino acids 3120-3422), which are characteristic of proteins involved in membrane trafficking and signalling.
Key variants
Variants in the LYST gene can alter the structure and function of the lysosomal trafficking regulator protein. These genetic changes can range from small alterations in DNA building blocks to larger deletions or insertions within the gene. Such variants may lead to a non-functional protein or one with impaired activity, disrupting the critical processes regulated by lysosomes.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.10643T>A | p.Leu3548Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.10883dup | p.Tyr3628Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.2016C>A | p.Tyr672Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.3996del | p.Asp1333fs | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.4433G>A | p.Trp1478Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.484C>T | p.Gln162Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.8156C>G | p.Ser2719Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.8425G>T | p.Glu2809Ter | Pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.9219_9222del | p.Glu3074fs | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
c.9245dup | p.Leu3082fs | Pathogenic/Likely pathogenic | ★★☆☆ | Chédiak-Higashi syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the LYST gene are primarily associated with Chediak-Higashi syndrome. This is an autosomal recessive disorder, meaning an individual must inherit two affected copies of the gene to develop the condition. These variants disrupt the normal size, structure, and function of lysosomes and related cellular structures, leading to a range of symptoms affecting multiple body systems.
- Chediak-Higashi-like (LYST)
- Chediak-Higashi syndrome Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic LYST variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The LYST gene is included in several expert-curated panels within the NHS Genomic Medicine Service's PanelApp. It is rated 'Green' for conditions such as Albinism or congenital nystagmus, Bleeding and platelet disorders, Primary immunodeficiency or monogenic inflammatory bowel disease, and Foetal anomalies. This indicates that there is strong evidence supporting the gene's association with these conditions for diagnostic purposes within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the LYST gene?
The LYST gene provides instructions for making a protein called the lysosomal trafficking regulator. This protein is believed to be important for managing the transport of materials into lysosomes, which are cellular compartments responsible for waste breakdown and recycling.
What condition is most commonly associated with LYST gene variants?
The condition most commonly associated with pathogenic variants in the LYST gene is Chediak-Higashi syndrome. This is an inherited disorder that affects various body systems due to impaired lysosomal function.
How is Chediak-Higashi syndrome inherited?
Chediak-Higashi syndrome is inherited in an autosomal recessive manner. This means that a person must inherit two altered copies of the LYST gene, one from each parent, to develop the condition.
References
- Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Current opinion in hematology. 2008. PMID: 18043242
- Westbroek W, Adams D, Huizing M. Cellular defects in Chediak-Higashi syndrome correlate with the molecular genotype and clinical phenotype. The Journal of investigative dermatology. 2007. PMID: 17554367
- Karim MA, Suzuki K, Fukai K. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. American journal of medical genetics. 2002. PMID: 11857544
- Tchernev VT, Mansfield TA, Giot L. The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins. Molecular medicine (Cambridge, Mass.). 2002. PMID: 11984006
- Ward DM, Shiflett SL, Kaplan J. Chediak-Higashi syndrome: a clinical and molecular view of a rare lysosomal storage disorder. Current molecular medicine. 2002. PMID: 12125812
- Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and Chediak-Higashi syndrome: disorders of vesicle formation and trafficking. Thrombosis and haemostasis. 2001. PMID: 11487012
- Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Molecular genetics and metabolism. 1999. PMID: 10527680