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C19orf12
chromosome 19 open reading frame 12
The C19orf12 gene encodes a mitochondrial membrane protein implicated in lipid homeostasis, with mutations linked to neurodegenerative disorders such as mitochondrial membrane protein-associated neurodegeneration (MPAN). The C19orf12 gene provides instructions for a protein located within the mitochondria, playing a role in maintaining cellular lipid balance.
C19orf12 is located on the long (q) arm of chromosome 19, at band 19q12. Arm ratio per GRCh38 - banding schematic.
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Overview
C19orf12, an abbreviation for chromosome 19 open reading frame 12, is a gene that codes for a protein found within the mitochondrial membrane. While its precise function is still under investigation, it is thought to be involved in lipid homeostasis, the process by which cells maintain a stable balance of fats.
Mutations in the C19orf12 gene are primarily associated with mitochondrial membrane protein-associated neurodegeneration (MPAN), a severe neurodegenerative disorder. Understanding the role of C19orf12 is crucial for diagnosing and researching conditions linked to mitochondrial dysfunction and iron accumulation in the brain.
What the gene does
The protein produced from the C19orf12 gene is localised to the membrane of mitochondria, which are vital cellular organelles responsible for energy production. Although its exact molecular role remains to be fully elucidated, research suggests that the C19orf12 protein contributes to lipid homeostasis. This process involves the regulation and maintenance of lipid molecules within the cell, which are essential for structural integrity, energy storage, and cellular signalling.
Disruption of this protein's function, often due to pathogenic variants, can lead to impaired mitochondrial function and cellular processes, particularly affecting neurological health. This dysfunction is believed to underlie the progressive neurodegeneration observed in associated conditions.
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Chromosome location
The C19orf12 gene is situated on chromosome 19 at band 19q12. This genomic location specifies where the gene can be found within the human genome. The gene encodes a protein that is 141 amino acids in length.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the C19orf12 gene can alter the protein's structure and function, leading to a range of clinical presentations. These genetic changes can include single nucleotide substitutions, small insertions, or deletions, which may result in a non-functional or improperly functioning protein. At least 28 different mutations have been identified that are associated with specific neurodegenerative conditions.
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.164_166delGGG | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 43 |
c.161G>A | p.Gly54Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation |
c.166del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia |
c.171_181del | p.Gly58fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal dominant C19orf12-related disorders |
c.172G>A | p.Gly58Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 43 |
c.205C>T | p.Gln69Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation 4 |
c.215C>T | p.Pro72Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 43 |
c.245del | p.Pro82fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation 4 |
c.-2C>T | T11M | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation 4 |
c.371dup | p.Met124fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation 4 |
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 C19orf12 gene are primarily linked to mitochondrial membrane protein-associated neurodegeneration (MPAN). This condition is characterised by progressive neurological symptoms, including movement disorders and cognitive decline, often accompanied by abnormal iron accumulation in specific brain regions. The clinical spectrum can also overlap with other neurodegenerative presentations.
No disease links recorded for this gene in our reference set.
UK clinical status
C19orf12 is included in several NHS Genomic Medicine Service clinical panels in the UK, indicating its importance in diagnosing neurological and metabolic conditions. It is part of panels for conditions such as "Dystonia, chorea or related movement disorder, adult onset" and "childhood onset", "Hereditary spastic paraplegia", "Early onset dystonia", and "Parkinson Disease and Complex Parkinsonism". It is also relevant for investigating "Likely inborn error of metabolism" and "Undiagnosed metabolic disorders".
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the C19orf12 gene?
The C19orf12 gene provides instructions for making a protein found in the membrane of mitochondria, the energy-producing centres of cells. This protein is thought to play a role in maintaining lipid homeostasis, which is the balance of fats within the cell.
What health conditions are associated with C19orf12?
Mutations in the C19orf12 gene are primarily associated with mitochondrial membrane protein-associated neurodegeneration (MPAN). This condition involves progressive movement and neurological problems, along with an abnormal accumulation of iron in certain parts of the brain.
How does C19orf12 relate to mitochondrial function?
The C19orf12 protein is located within the mitochondrial membrane. Its suggested role in lipid homeostasis is critical for proper mitochondrial function, as lipids are essential components of mitochondrial membranes and energy metabolism. Disruptions can therefore impact overall mitochondrial health.
References
- Kruer MC, Salih MA, Mooney C. C19orf12 mutation leads to a pallido-pyramidal syndrome. Gene. 2014. PMID: 24361204
- Dogu O, Krebs CE, Kaleagasi H. Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration. Clinical genetics. 2013. PMID: 23278385
- Landouré G, Zhu PP, Lourenço CM. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Human mutation. 2013. PMID: 23857908
- Deschauer M, Gaul C, Behrmann C. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. Journal of neurology. 2012. PMID: 22584950
- Hartig MB, Iuso A, Haack T. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. American journal of human genetics. 2011. PMID: 21981780