Huntington's disease-like

A particular type of variant (also called a mutation) in the PRNP gene has been found to cause a condition called Huntington's disease-like 1 (HDL1). The signs and symptoms of HDL1 resemble those of a more common condition called Huntington's disease.These signs and symptoms include uncontrolled movements, emotional problems, and a loss of thinking ability.

The type of variant associated with HDL1 involves a segment of DNA that provides instructions for making a protein fragment called an octapeptide. The octapeptide is made of eight protein building blocks (amino acids). In the PRNP gene, this segment is normally repeated four times. In people with HDL1, this segment is repeated six or more times. An increase in the size of the octapeptide repeat leads to the production of an abnormally long version of PrP. Studies have found a buildup of PrP protein in various areas of the brain in people with HDL1, which likely contributes to the loss of neurons and causes the features of HDL1.

Prion disease

Many variants in the PRNP gene have been identified in people with familial forms of prion disease, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). The major features of these diseases include changes in memory, personality, and behavior; a decline in intellectual function (dementia); and poor coordination and balance (ataxia). The signs and symptoms worsen over time, ultimately leading to death.

Some of the PRNP gene variants that cause familial prion disease change single amino acids in PrP. Other variants insert additional amino acids into the protein or cause the cell to produce an unusually short version of the protein. These changes alter the structure of PrP, leading to the production of PrP^Sc. In a process that is not fully understood, PrP^Sc can attach (bind) to PrP^C and transform it into PrP^Sc. The abnormal protein builds up in the brain, forming clumps that damage or destroy neurons. The loss of these cells creates microscopic sponge-like holes (vacuoles) in the brain, which leads to the signs and symptoms of prion disease.

Researchers have identified several common variations (polymorphisms) in the PRNP gene that affect single amino acids in PrP. These polymorphisms do not cause prion disease, but they may affect a person's risk of developing these disorders. Studies have focused on the effects of a polymorphism at position 129 of PrP. At this position, people can have either the amino acid methionine (Met) or the amino acid valine (Val). This polymorphism is written as Met129Val or M129V. Because people inherit one copy of the PRNP gene from each parent, an individual can receive methionine from both parents (Met/Met), valine from both parents (Val/Val), or methionine from one parent and valine from the other (Met/Val).

The Met129Val polymorphism appears to influence a person's risk of developing prion disease. Most affected individuals have the same amino acid at position 129 (Met/Met or Val/Val) instead of different amino acids (Met/Val). People with Met/Met at position 129 are more likely to develop prion disease earlier in life and experience rapid worsening of the disease's signs and symptoms.

Wilson disease

The Met129Val polymorphism has also been reported to influence the onset of Wilson disease, an inherited disorder in which excessive amounts of copper build up in the body.  Wilson disease is caused by variants in the ATP7B gene, but studies suggest that symptoms of Wilson disease begin several years later in people who have Met/Met at position 129 in PrP compared with those who have Met/Val or Val/Val. Other research findings indicate that this polymorphism may also affect the type of symptoms that develop in people with Wilson disease. People with Met/Met at position 129 appear to be more likely to have symptoms that affect the nervous system, particularly tremors.

Other disorders

The Met129Val polymorphism has been associated with differences in performance on long-term memory tasks among healthy young adults. In one study, people who had either Met/Met or Met/Val at position 129 performed better at long-term memory tasks than those who had Val/Val. It is unclear how these differences may be related to memory.