TRIPLET REPEAT DISORDERS

Question 1

Biparental inheritance

Answer 1

one allele from each parent

Question 2

The phenotype is controlled by the action of one, and

Answer 2

only one,
gene (sequence variation at only one locus is necessary and
sufficient to bring about phenotype change)

Question 3

Stable inheritance of mutations

Answer 3

parent and child have the

identical DNA change

Question 4

An interesting group of disorders was described

Answer 4

A small group, particularly neuromuscular/neurodegenerative disorders

Question 5

followed rules of Mendelian inheritance

Answer 5

Single gene disorders

Question 6

example of disorders that followed mendelian rules

Answer 6

• Fragile X syndrome (Xq27): FMR1 gene X-linked
• Myotonic Dystrophy (19q13): DMPK gene Autosomal dominant
• Huntington disease (4p16): HTT gene Autosomal dominant
• Friedreich’s ataxia (9q21) FXN gene Autosomal recessive
• Spinocerebellar ataxias

Question 7

non-mendelian

Answer 7

But phenotypically, it was noted that clinical disease in offspring could be more severe than in the transmitting parent (siblings could also be very differently affected); further
age at onset in offspring could be earlier as compared to transmitting parent

Question 8

repeats occur throughout the
genome; repeat units come in different sizes; repeat length is
polymorphic; most repeats do not occur in functional regions
of the genome and they have no phenotypic effect

Answer 8

true

Question 9

TRDs: Molecular basis

Answer 9

• Number of repeats varies
– between individuals
– on different chromosomes
• Part of normal variation

Question 10

Stable Mendelian inheritance in families (a child

will inherit one allele from each parent)

Answer 10

true

Question 11

in 1990

Answer 11

It was discovered that in all these disorders, the gene
involved had an associated repeat sequence. The repeat was
usually always a 3 nucleotide/triplet repeat (hence – ‘triplet
repeat disorders’).
• In all affected individuals, the number of repeat units was
above a certain threshold (expansion of the repeat resulted in
disease).
• This instability in genetic transmission was outside the central
the dogma of molecular biology and presented a new type of
mutation mechanism!

Question 12

Repeats are dynamic

Answer 12

During cell division, a mistake can be made by the DNA
polymerase, and the daughter cell will contain more repeats
than the parent cell. Repeat size changes from one
generation to the next; repeats can be ‘dynamic’.

Question 13

Triplet repeat disorders both obey

and deviate from Mendel’s rules

Answer 13

• However, because certain patterns of inheritance cannot
be explained only on the basis of Mendel’s laws
– Fall into a category referred to as non-Mendelian inheritance
• Do NOT disobey Mendelian principles but cannot be
explained by these principles alone

Question 14

Triplet Repeat Disorders (TRDs)

• Characterised within and between families by:

Answer 14

• Variable disease presentation and progression
• Anticipation which is defined as
‒ Earlier age of onset
‒ Increased severity in successive generations

Question 15

TRDs: Molecular basis-Threshold concept

Answer 15

• Repeat number above threshold results in disease

* Different for different disorders

Question 16

TRDs: Molecular basis-The mutation is dynamic

Answer 16

• Tends to increase in repeat number between generations

* Initial change predisposes to further change

Question 17

TRDs: Molecular basis-Instability becomes manifest

Answer 17

• Individuals within a single-family have different repeat numbers
• In the same individual, different tissues have different repeat
numbers

Question 18

Position of repeats

Answer 18

Repeats may be intragenic (within the exon or intron) or extragenic
(5’ or 3’ of the gene)

Question 19

If present within exons:

Answer 19

• Encode a series of identical amino acids, translated to protein
• Gain-of-function

Question 20

If present in the UTR:

Answer 20

• Disrupt transcription, translation, or protein function

* Loss-of-function

Question 21

• Coding repeats

Answer 21

– Commonly CAG
• Code for the amino acid glutamine (Q)
• Polyglutamine (or poly Q) diseases
– Gain-of-function mutations
• Mutant protein has a toxic effect

Question 22

Non-coding repeats

Answer 22

– Variable: CGG, GCC, GAA, CTG, or CAG
– Very large repeat expansions
– Usually loss-of-function mutations

Question 23

Diseases with (CAG)n repeats in coding regions

Answer 23

– Huntington disease (HD)
– Spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7
– Spinobulbar muscular atrophy (Kennedy’s disease)

Question 24

Diseases with non-coding repeats:

Answer 24

– Fragile X syndrome (CGG repeat)
– Myotonic dystrophy (DM) (CTG repeat)
– Friedreich ataxia (GAA repeat)