http://ghr.nlm.nih.

gov/gene/PRNP

What is prion disease?

Prion disease represents a group of conditions that affect the nervous system in humans and
animals. In people, these conditions impair brain function, causing
changes in memory, personality, and behavior;
a decline in intellectual function (dementia);
and abnormal movements, particularly difficulty with coordinating movements
(ataxia).
The signs and symptoms of prion disease typically begin in adulthood and worsen with time,
leading to death within a few months to several years.

How common is prion disease?

These disorders are very rare. Although the exact prevalence of prion disease is unknown,
studies suggest that this group of conditions affects about one person per million worldwide
each year. Approximately 350 new cases are reported annually in the United States.

What genes are related to prion disease?

Between 10 and 15 percent of all cases of prion disease are caused by mutations in the PRNP
gene. Because they can run in families, these forms of prion disease are classified as familial.
Familial prion diseases, which have overlapping signs and symptoms, include familial
Creutzfeldt-Jakob disease (CJD), Gerstmann-Strussler-Scheinker syndrome (GSS), and fatal
familial insomnia (FFI).
The PRNP gene provides instructions for making a protein called prion protein (PrP). Although
the precise function of this protein is unknown, researchers have proposed roles in several
important processes. These include the transport of copper into cells, protection of brain cells
(neurons) from injury (neuroprotection), and communication between neurons. In familial forms
of prion disease,PRNP gene mutations result in the production of an abnormally shaped protein,
known as PrPSc, from one copy of the gene. In a process that is not fully understood, PrPSc can
attach (bind) to the normal protein (PrPC) and promote its transformation into PrPSc. 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.
The other 85 to 90 percent of cases of prion disease are classified as either sporadic or
acquired. People with sporadic prion disease have no family history of the disease and no
identified mutation in the PRNP gene. Sporadic disease occurs when PrPC spontaneously, and
for unknown reasons, is transformed into PrPSc. Sporadic forms of prion disease include
sporadic Creutzfeldt-Jakob disease (sCJD), sporadic fatal insomnia (sFI), and variably
protease-sensitive prionopathy (VPSPr).
Acquired prion disease results from exposure to PrPSc from an outside source. For example,
variant Creutzfeldt-Jakob disease (vCJD) is a type of acquired prion disease in humans that
results from eating beef products containing PrPSc from cattle with prion disease. In cows, this
form of the disease is known as bovine spongiform encephalopathy (BSE) or, more commonly,
"mad cow disease." Another example of an acquired human prion disease is kuru, which was
identified in the South Fore population in Papua New Guinea. The disorder was transmitted
when individuals ate affected human tissue during cannibalistic funeral rituals.
Rarely, prion disease can be transmitted by accidental exposure to PrPSc-contaminated tissues
during a medical procedure. This type of prion disease, which accounts for 1 to 2 percent of all
cases, is classified as iatrogenic.
Read more about the PRNP gene.

How do people inherit prion disease?

Familial forms of prion disease are inherited in an autosomal dominant pattern, which means
one copy of the altered PRNP gene in each cell is sufficient to cause the disorder. In most
cases, an affected person inherits the altered gene from one affected parent. In some people,
familial forms of prion disease are caused by a new mutation in the gene that occurs during the
formation of a parent's reproductive cells (eggs or sperm) or in early embryonic development.
Although such people do not have an affected parent, they can pass the genetic change to their
children.
The sporadic, acquired, and iatrogenic forms of prion disease, including kuru and variant
Creutzfeldt-Jakob disease, are not inherited.

What is the official name of the PRNP gene?

The official name of this gene is prion protein.
PRNP is the gene's official symbol. The PRNP gene is also known by other names, listed below.
Read more about gene names and symbols on the About page.

What is the normal function of the PRNP gene?

The PRNP gene provides instructions for making a protein called prion protein (PrP), which is
active in the brain and several other tissues. Although the precise function of this protein is
unknown, researchers have proposed roles in several important processes. These include the
transport of copper into cells and protection of brain cells (neurons) from injury
(neuroprotection). Studies have also suggested a role for PrP in 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. The normal version is often designated PrPC to
distinguish it from abnormal forms of the protein, which are generally designated PrPSc.

Does the PRNP gene share characteristics with other genes?

The PRNP gene belongs to a family of genes called CD (CD molecules).
A gene family is a group of genes that share important characteristics. Classifying individual
genes into families helps researchers describe how genes are related to each other. For more
information, see What are gene families? in the Handbook.

How are changes in the PRNP gene related to health conditions?

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. Researchers have proposed that this condition be called
Huntington disease-like 1 (HDL1).
The PRNP mutations associated with HDL1 involve 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.
prion disease - caused by mutations in the PRNP gene
More than 30 mutations in the PRNP gene have been identified in people with familial forms of
prion disease, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Strussler-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
abnormal movements, particularly difficulty with coordinating movements (ataxia). The signs and
symptoms worsen over time, ultimately leading to death.
Some of the PRNP gene mutations that cause familial prion disease change single amino acids
in PrP. Other mutations insert additional amino acids into the protein or result in an unusually
short version of the protein. These changes alter the structure of PrP, leading to the production
of an abnormally shaped protein, known as PrPSc, from one copy of the PRNP gene. In a
process that is not fully understood, PrPSc can attach (bind) to PrPC and promote its
transformation into PrPSc. 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, at position 129
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 the 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). Having Met/Met at position 129 is also associated with an earlier
age of onset and a more rapid worsening of the disease's signs and symptoms.
Wilson disease - course of condition modified by normal variations in the PRNP gene
The Met129Val polymorphism has been reported to influence 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 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.
Having Met/Met at position 129 appears to be associated with an increased occurrence of
symptoms that affect the nervous system, particularly tremors.
other disorders - associated with the PRNP gene
The Met129Val variation 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.

Where is the PRNP gene located?

Cytogenetic Location: 20p13
Molecular Location on chromosome 20: base pairs 4,686,150 to 4,701,587

The PRNP gene is located on the short (p) arm of chromosome 20 at position 13.
More precisely, the PRNP gene is located from base pair 4,686,150 to base pair 4,701,587 on
chromosome 20.

http://www.ncbi.nlm.nih.gov/books/NBK1229/

Clinical Diagnosis
Genetic prion diseases constitute a continuum of clinical manifestations, originally labeled as
familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Strussler-Scheinker (GSS) syndrome,
and fatal familial insomnia (FFI). Note: A fourth clinical phenotype, known as Huntington disease
like-1 (HDL-1), has been proposed, but this is based on a limited number of cases, and the
underlying pathologic features would categorize it as GSS [Moore et al 2001]. It is now known
that these phenotypes are not distinct entities but rather constitute a spectrum of clinical and
pathologic manifestations of genetic prion disease; nonetheless, certain aspects of these
phenotypes are useful in diagnosis and care. There are no formal diagnostic criteria established
for the genetic forms of disease, although criteria do exist for the non-genetic form of CJD (see
end of this section), which can be used as a general framework for approaching these diseases.
The diagnosis of genetic prion disease requires a combination of the following:
Clinical features comprising varying combinations of adult-onset neurologic signs
and symptoms, including:
Dementia
Psychiatric symptoms
Dyscoordination of movements (ataxia, dysarthria)
Myoclonus (muscle jerks)
 Weakness and/or spasticity
Chorea
Stroke-like episodes
Seizures
Autonomic disturbances
Neuropathologic findings include:
Spongiform degeneration and astrogliosis diffusely distributed
throughout the cortex and deep nuclei of the brain (fCJD)
Multiple amyloid plaques to which anti-prion protein (PrP)
antibodies bind (GSS)
A relative lack of spongiform degeneration and presence of
neuronal dropout and gliosis primarily within the thalamus and inferior olivary
nucleus of the brain stem (FFI) [DeArmond & Prusiner 1997]
Family history consistent with autosomal dominant inheritance
A PRNP disease-causing mutation (see Molecular Genetic Testing)

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