Biology of Disease

INHERITED GENE DISORDERS

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BOX 15.1 Spongiform encephalopathies or prion diseases

The spongiform encephalopathies (SEs) or prion diseases (Table
15.2) are a rather peculiar group of diseases that can be inherited
although this is not their usual method of transmission. It was
noted in Chapter 2 that these are infectious diseases but also
have a low sporadic occurrence of about one in a million for CJD.
However, they are unusual in that they can also be familial, that
is they are also inherited (genetic) diseases. Irrespective of cause,
these diseases generally develop slowly over 10 to 20 years in
older individuals and are characterized by the presence of holes
or plaques in brain tissue that can only be observed postmortem,
giving it a spongy appearance (Figure 15.13), hence the name
spongiform. There are no cures for these diseases and all are
fatal. Variant CJD, which first appeared in the UK in the 1980s,
differs from ‘conventional’ CJD in that it occurs in younger people

and death occurs relatively rapidly within about 2 years following

the first appearance of symptoms.

Prions are proteins that are normally found in a predominantly A

helical conformation, the native form. However, these molecules

can change shape to a form with an increased B sheet content

that is a pathological conformation (Figure 15.14). In a poorly

understood manner, the B sheet-rich prion protein somehow

induces conformational changes in native A helical-rich

molecules to change them to the B type conformation. These

newly misfolded molecules can, in turn, stimulate conformational

changes in other molecules in a chain reaction that deposits

aggregates of prions in the brain leading to the destruction of

neurons and finally the lethal spongiform condition. Thus SEs are

a subdivision of a group of diseases called protein conformational

diseases.

The sporadic forms of these diseases occur in individuals with

point mutations in the gene that encodes the prion protein.

These mutations alter the sequence of amino acid residues in the

prion protein molecules and predispose them to misfold to the

B sheet-rich, pathological form. Different mutations in the gene

are associated with different SEs (Table 15.3). The mutations

are, of course, heritable but since the symptoms of the diseases

usually only become apparent after reproductive life is over, they

can run in families producing the familial forms of the disease.

Name of disease

Atypical dementias

Creutzfeldt-Jacob disease (CJD)

Variant Creutzfeldt-Jacob disease (vCJD)

Fatal familial insomnia (FFI)

Gerstmann-Sträussler-Scheinker disease (GSS)

Kuru

Table 15.2Examples of human spongiform encephalopathies or prion diseases

Figure 15.13 (A) The distinctive spongiform appearance of the cortex of the brain
associated with CJD and (B) Aggregates of the pathological form of the protein
deposited in the cerebellum. Courtesy of National CJD Surveillance Unit, UK.

Mutation Disease

Pro102Leu GSS

Pro105Leu GSS

Ala117Val GSS

Tyr145Stop GSS

Asp178Asn familial CJD, FFI

Val180Ile GSS

Phe198Ser GSS

Glu200Lys familial CJD

Arg208His CJD

Val210Ile familial CJD

Gln217Arg GSS

Met232Arg GSS(?)

Octarepeat insert familial CJD

Table 15.3Some mutations of the human prion protein

associated with spongiform encephalopathies

Figure 15.14 Schematic to show the change in conformation of the

normal (@ helical-rich) prion protein to the pathological (A sheet-rich)

conformation.

Conversion

during disease

Normal conformation Pathological conformation

A) B)