PRNP

The PRNP gene provides instructions for making a protein called the prion protein (PrP), which is active in the brain and several other tissues. Although the precise function of PrP is unknown, it is probably involved in the transport of charged copper atoms (copper ions) into cells. Researchers have also proposed roles for PrP in cell signaling, cell protection, and the formation of synapses, which are the junctions between nerve cells (neurons) where cell-to-cell communication occurs.

Different forms of PrP have been identified in the nervous system. The usual cellular form is often called PrP^C.

Huntington disease-like syndrome - caused by mutations in the PRNP gene

A particular type of mutation in the PRNP gene has been found to cause signs and symptoms that resemble those of Huntington disease, including uncontrolled movements, emotional problems, and loss of thinking ability. This condition, which has been described in a single family, is known as Huntington disease-like 1 (HDL1).

The PRNP mutation associated with HDL1 involves a segment of DNA called an octapeptide repeat. This segment provides instructions for making eight protein building blocks (amino acids) that are linked to form a protein fragment called a peptide. The octapeptide repeat is normally repeated five times in the PRNP gene. In people with HDL1, this segment is repeated eleven or thirteen times. An increase in the size of the octapeptide repeat leads to the production of an abnormally long version of PrP. It is unclear how the abnormal protein damages and ultimately destroys neurons, leading to the characteristic features of HDL1. This disorder appears to be a prion disease similar to classic Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome (see below).

prion disease - caused by mutations in the PRNP gene

More than 30 mutations in the PRNP gene have been identified in people with familial prion diseases, including classic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal insomnia. Mutations in this gene have also been found in affected individuals without a family history of prion disease.

Some PRNP mutations change single amino acids in PrP. Other mutations insert additional amino acids into the protein or result in an atypically short version of the protein. These changes alter the structure of PrP, leading to the production of an abnormal protein known as PrP^Sc from one copy of the PRNP gene. In a process that is not fully understood, PrP^Sc can promote the transformation of the normal prion protein, PrP^C, into more 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 in the brain, which leads to the mental and behavioral features of prion diseases.

Researchers have identified several common variations (polymorphisms) in the PRNP gene that change an amino acid in PrP. These polymorphisms do not cause prion diseases, but may affect a person's risk of developing these disorders. Studies have focused on the effects of a polymorphism at position 129 of PrP, which may have either the amino acid methionine (Met) or the amino acid valine (Val). (This polymorphism is written as Met129Val or M129V.) The risk of developing Creutzfeldt-Jakob disease and other prion diseases may depend in part on whether the individual has inherited the same polymorphism at position 129 from both parents. This polymorphism may also contribute to the disease's age of onset and the course of signs and symptoms.

Wilson disease - course of condition modified by normal variations in the PRNP gene

The Met129Val polymorphism appears to delay the onset of Wilson disease, an inherited disorder in which excessive amounts of copper accumulate in the body. Wilson disease is caused by mutations in the ATP7B gene, but research studies suggest that symptoms of Wilson disease begin several years later in people who have methionine (instead of valine) at position 129 in the PrP protein. Other research findings indicate that the Met129Val polymorphism may also affect the type of symptoms that develop in people with Wilson disease. Methionine, instead of valine, at PrP position 129 appears to be associated with an increased occurrence of symptoms that affect the nervous system, particularly tremors. Larger studies are needed, however, before the effects of the Met129Val polymorphism on Wilson disease can be established.

other disorders - associated with the PRNP gene

The Met129Val polymorphism in the PRNP gene has been associated with a form of dementia called primary progressive aphasia. This condition involves a gradual loss of language function, including reading, writing, and speaking, beginning in middle age. As the disorder progresses, it affects other brain functions as well. The Met129Val variation also has been associated with differences in performance on long-term memory tasks among healthy young adults.