Theme: iWiki Log in Register

Diff: C9orf72

Comparing revision #1 (2023-06-15 04:54:16) with revision #2 (2026-06-22 09:08:30).

Old	New
	'''C9orf72''' is a human gene on chromosome 9. It is best known because an expanded repeat in the gene is a major genetic cause of [[amyotrophic lateral sclerosis]] (ALS), [[frontotemporal dementia]] (FTD), and mixed ALS-FTD.

C9orf72 is a gene located on [[chromosome 9]] that has gained significant attention in the field of neurogenetics due to its association with several [[Neurodegenerative disorder\|neurodegenerative disorders]]. This gene is known for its role in both familial and sporadic cases of [[Amyotrophic Lateral Sclerosis (ALS)\|amyotrophic lateral sclerosis (ALS)]] and [[frontotemporal dementia]] (FTD), two closely related conditions that affect the nervous system.
	The name originally meant "chromosome 9 open reading frame 72". Modern gene resources describe it as the C9orf72-SMCR8 complex subunit. The gene is active in several tissues and is especially important in neurons, including motor neurons and neurons in the cerebral cortex.

== Gene Structure and Function ==
The C9orf72 gene spans a region on [[chromosome 9q21.32]] and consists of several exons. Its exact function is not yet fully understood, although research suggests that it plays a role in normal cellular processes, including protein transport and autophagy. The gene produces a protein known as C9orf72, although its precise function within the cell is still being investigated.
	== Normal Function ==
	C9orf72 provides instructions for making a protein involved in normal cell processes. MedlinePlus Genetics describes the protein as abundant in nerve cells in the outer layers of the brain and in motor neurons in the brain and spinal cord.

== C9orf72 Mutations ==
Mutations in the C9orf72 gene are the most common known cause of both familial and sporadic cases of ALS and FTD. The mutations involve an abnormal expansion of a repeated DNA sequence within the gene. The normal version of the C9orf72 gene contains a short repeating sequence of six nucleotides, represented as GGGGCC. However, in individuals with C9orf72 mutations, this repeat expansion can occur hundreds or even thousands of times, leading to the formation of unusual structures within the gene.
	The exact range of C9orf72 functions is still being studied. Current work links it with RNA handling, protein production, intracellular transport, autophagy, endosomal trafficking, and the handling of cellular material inside membrane-bound compartments.

These repeat expansions can disrupt normal gene expression and cause problems in RNA processing, which ultimately results in the accumulation of abnormal RNA and protein aggregates within neurons. The presence of these aggregates is believed to contribute to the degeneration of motor neurons in ALS and the loss of brain tissue in FTD.
	== Repeat Expansion ==
	The clinically important C9orf72 change is a hexanucleotide repeat expansion. The repeated sequence is GGGGCC, sometimes written as G4C2. A small number of repeats can be part of normal variation. A much larger repeat expansion can be pathogenic.

== Inheritance and Genetic Testing ==
C9orf72 mutations can be inherited in an autosomal dominant manner, which means that a single copy of the mutated gene is sufficient to cause disease. Offspring of an affected individual have a 50% chance of inheriting the mutation. However, it is important to note that some cases of ALS and FTD associated with C9orf72 mutations can occur spontaneously without a family history of the disease.
	This expansion is not a simple spelling error in the gene. It can affect cells in more than one way. Proposed mechanisms include reduced normal C9orf72 protein function, toxic RNA effects, abnormal dipeptide repeat proteins, disturbed RNA processing, impaired protein handling, and stress within neurons.

Genetic testing for C9orf72 mutations is available and can be used to confirm a diagnosis and provide information about an individual's genetic risk. Testing methods include polymerase chain reaction (PCR) and repeat-primed PCR, which can detect the presence of expanded repeat sequences in the gene.
	Motor neurons and frontal or temporal brain networks appear especially vulnerable, which helps explain the link with ALS and FTD.

	== Associated Conditions ==
	C9orf72 repeat expansion is associated mainly with:

	* Amyotrophic lateral sclerosis, a motor neuron disease causing progressive weakness and loss of motor function.
	* Frontotemporal dementia, a group of disorders affecting behaviour, executive function, language, personality, and social judgement.
	* ALS-FTD, where features of both conditions occur in the same person.

	GeneReviews describes C9orf72-FTD/ALS as most often involving FTD and upper and lower motor neuron disease, although atypical presentations can occur. Age at onset is often between 50 and 64 years, but reported ranges are much wider.

== Clinical Features ==	== Clinical Features ==
The presence of C9orf72 mutations can lead to a wide range of clinical manifestations. In ALS, individuals with C9orf72 mutations often experience a combination of upper and lower motor neuron signs, such as muscle weakness, muscle atrophy, and spasticity. They may also exhibit features of FTD, including changes in behavior, personality, and language abilities.
	The presentation is variable. Some people develop mainly motor symptoms. Others develop cognitive, language, behavioural, or psychiatric symptoms first.

C9orf72-associated ALS and FTD can present with variable age of onset and disease progression. Some individuals may develop symptoms in their 40s or 50s, while others may experience an earlier or later onset. The disease course can also vary, with some individuals experiencing a more rapid progression, while others have a more indolent course.
	ALS features can include:

== Research and Therapeutic Strategies ==
The discovery of C9orf72 mutations has provided valuable insights into the underlying mechanisms of ALS and FTD. It has opened up new avenues for research and potential therapeutic strategies. Scientists are actively investigating the specific mechanisms by which the expanded repeat sequences lead to neuronal dysfunction and exploring potential therapeutic targets.
	* Progressive limb weakness.
	* Bulbar symptoms such as speech or swallowing difficulty.
	* Muscle wasting or fasciculations.
	* Stiffness, spasticity, or brisk reflexes.
	* Respiratory weakness in advanced disease.

Various approaches are being explored to develop treatments for C9orf72-associated ALS and FTD. These include gene silencing techniques, antisense oligonucleotide therapies, and small molecule drugs aimed at reducing the accumulation of toxic RNA and protein aggregates. Clinical trials are underway to evaluate the safety and efficacy of these potential treatments.
	FTD features can include:

	* Personality and behaviour change.
	* Loss of judgement or social awareness.
	* Apathy, disinhibition, or compulsive behaviour.
	* Language difficulty.
	* Executive dysfunction, including planning and problem solving.
	* Memory problems in some cases.

	C9orf72-related disease can differ between relatives carrying the same expansion. One family member may develop ALS, another may develop FTD, and another may remain unaffected into later life.

	== Inheritance ==
	C9orf72-FTD/ALS is usually inherited in an autosomal dominant pattern. This means a person with a pathogenic expansion has a 1 in 2 chance of passing it to each child.

	Penetrance is age-related and incomplete. In plain terms, inheriting the expansion increases risk substantially, but it does not guarantee that symptoms will appear by a particular age. Genetic counselling is therefore important before predictive testing in an unaffected person.

	== Genetic Testing ==
	Testing for C9orf72 repeat expansion is a specialist genetic test. Standard sequencing panels may not detect repeat expansions reliably, so the requested method matters.

	Testing may be considered when a person has ALS, FTD, ALS-FTD, a strong family history, or a clinical pattern suggestive of inherited neurodegenerative disease. Results can affect family counselling, eligibility for research, and future trial options, but they can also have major psychological and insurance implications.

	== Research ==
	C9orf72 became central to ALS and FTD research after separate 2011 studies identified the repeat expansion as a cause of chromosome 9p-linked ALS and FTD. Since then, research has focused on how the expansion damages neurons and whether targeted therapies can reduce toxic RNA, toxic proteins, or downstream cellular stress.

	Approaches under investigation include antisense oligonucleotides, gene-silencing strategies, disease biomarkers, and treatments aimed at common pathways in ALS and FTD. These remain specialist research areas rather than routine cures.

	== See Also ==
	* [[Frontotemporal dementia]]
	* [[Neurodegenerative disorder]]
	* [[Chromosome_9]]
	* [[TRPV4]]

== References ==	== References ==
	* [https://medlineplus.gov/genetics/gene/c9orf72/ MedlinePlus Genetics: C9orf72 gene]
	* [https://www.ncbi.nlm.nih.gov/books/NBK268647/ GeneReviews: C9orf72 frontotemporal dementia and amyotrophic lateral sclerosis]
	* [https://pubmed.ncbi.nlm.nih.gov/21944778/ DeJesus-Hernandez et al., Neuron, 2011]
	* [https://pubmed.ncbi.nlm.nih.gov/21944779/ Renton et al., Neuron, 2011]

# DeJesus-Hernandez M, et al. (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked FTD and ALS. Neuron, 72(2), 245-256.
# Renton AE, et al. (2011). A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron, 72(2), 257-268.
# Majounie E, et al. (2012). Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol, 11(4), 323-330.
	[[Category:Genetics]]
	[[Category:Medicine]]
	[[Category:Neurology]]