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PLP1
proteolipid protein 1
The PLP1 gene provides instructions for producing proteolipid protein 1, which is vital for forming the myelin sheath that insulates nerve fibres in the central nervous system. PLP1 is located on the X chromosome and is essential for the proper development and maintenance of myelin, the protective fatty layer around nerve cells.
PLP1 is located on the long (q) arm of chromosome X, at band Xq22.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The PLP1 gene, or proteolipid protein 1, is crucial for the healthy functioning of the nervous system. It plays a key role in the production of two proteins, proteolipid protein 1 and a modified version called DM20, both of which are fundamental components of myelin.
Myelin is a fatty sheath that insulates nerve fibres, allowing for rapid and efficient transmission of nerve impulses throughout the body. The PLP1 gene's contribution to myelin stability is essential for proper neurological function.
What the gene does
The PLP1 gene codes for two proteins: proteolipid protein 1 and its isoform, DM20. Proteolipid protein 1 is predominantly found in the central nervous system, which includes the brain and spinal cord. DM20 is mainly present in the peripheral nervous system, which consists of the nerves connecting the brain and spinal cord to muscles and other parts of the body.
These proteins are located within the cell membranes of oligodendrocytes, specialised cells responsible for creating myelin. Myelin acts as an electrical insulator, promoting the swift transmission of nerve impulses. Proteolipid protein 1 and DM20 constitute a significant proportion of myelin and are vital for anchoring this protective layer to the nerve cells, ensuring its structural integrity and proper function.
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Chromosome location
The PLP1 gene is situated on the X chromosome, specifically at position Xq22.2. This genomic location means that the gene is X-linked. It spans a region that contributes to the genetic instructions for a protein comprising 277 amino acids.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the PLP1 gene can alter the protein's structure or production, leading to impaired myelin formation or maintenance. Hundreds of different variants have been identified, each potentially impacting the gene's function to varying degrees and resulting in a spectrum of clinical presentations.
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 |
|---|---|---|---|---|
GRCh37/hg19 Xq22.2(chrX:103031924-103044327)x1 | - | Pathogenic | ★☆☆☆ | not provided |
GRCh37/hg19 Xq22.2(chrX:103031924-103045526)x2 | - | Pathogenic | ★☆☆☆ | Pelizaeus-Merzbacher disease |
g.(?_103031003)_(103031929_?)del | - | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 2 |
g.(?_103031767)_(103047549_?)dup | - | Pathogenic | ★☆☆☆ | Pelizaeus-Merzbacher disease |
g.(?_103031893)_(103045536_?)dup | - | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 2 |
g.(?_103031893)_(103045546_?)del | - | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 2 |
g.(?_103031924)_(103045526_?)del | - | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 2 |
g.(?_103031924)_(103045526_?)dup | - | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 2 |
g.(?_103040922)_(103042832_?)del | - | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 2 |
g.(?_103042707)_(103045526_?)del | - | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 2 |
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
Variations in the PLP1 gene are associated with several inherited neurological disorders, primarily affecting males due to its X-linked inheritance pattern. These conditions include Pelizaeus-Merzbacher disease, which involves significant central nervous system impairment, and spastic paraplegia type 2, characterised by progressive muscle stiffness and weakness in the lower limbs. Both conditions are linked to issues with myelin integrity.
Inheritance pattern
Conditions caused by pathogenic PLP1 variants typically follow X-linked inheritance.
Carrier frequency by population How common is heterozygous PLP1 carrier status across ancestry groups?UK clinical status
The PLP1 gene is recognised within the UK's National Health Service (NHS) Genomic Medicine Service. It is listed as 'green' in several NHS England National Genomic Test Directory panels, including those for hereditary spastic paraplegia (both adult and childhood onset), inherited white matter disorders, and intellectual disability. This indicates that PLP1 is considered a gene for which there is sufficient evidence for routine clinical testing within these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PLP1 gene?
The PLP1 gene provides instructions for producing proteolipid protein 1 and DM20, which are essential components of myelin. Myelin is a fatty sheath that insulates nerve fibres, enabling rapid nerve impulse transmission.
Which conditions are associated with variants in the PLP1 gene?
Variants in the PLP1 gene are primarily associated with Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Both are neurological conditions characterised by issues with myelin.
Why are conditions linked to PLP1 variants more common in males?
PLP1 is located on the X chromosome, meaning it has an X-linked inheritance pattern. Males have only one X chromosome, so a single altered copy of the gene is usually sufficient to cause the condition.
References
- Mierzewska H, Jamroz E, Mazurczak T. Pelizaeus-Merzbacher disease in patients with molecularly confirmed diagnosis. Folia neuropathologica. 2016. PMID: 27179222
- Xie H, Feng H, Ji J. Identification and functional study of novel PLP1 mutations in Chinese patients with Pelizaeus-Merzbacher disease. Brain & development. 2015. PMID: 25491635
- Torii T, Miyamoto Y, Yamauchi J. Pelizaeus-Merzbacher disease: cellular pathogenesis and pharmacologic therapy. Pediatrics international : official journal of the Japan Pediatric Society. 2014. PMID: 25040584
- Garbern JY. Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis. Cellular and molecular life sciences : CMLS. 2007. PMID: 17115121
- Garbern JY. Pelizaeus-Merzbacher disease: pathogenic mechanisms and insights into the roles of proteolipid protein 1 in the nervous system. Journal of the neurological sciences. 2005. PMID: 15694206
- Adam MP, Bick S, Mirzaa GM. PLP1-Related Disorders. 1993. PMID: 20301361