Trinucleotide Repeat Disorders

Question 1

Principles of TNR Disorders

Answer 1

Molecular characteristics and consequences of expansion differ.

The tendency for repeat expansion depends on the TRANSMITTING PARENT.

Individuals with an abnormal # of TNRs who have fewer or no symptoms are said to carry PREMUTATIONS.

TNR disorders display GENETIC ANTICIPATION.

Question 2

Polyglutamine diseases are caused by excess _____ _____ due to glutamine insertions.

Examples: ______ and ______

Answer 2

Polyglutamine diseases are caused by excess MISFOLDED PROTEIN due to glutamine insertions.

Examples: HUNTINGTONS and SPINOCEREBELLAR ATAXIA

Question 3

Genetic anticipation is defined as follows:

As TNRs expand with ______ ______, the disease presents at an ____ age, and demonstrates an _______ _____ clinical phenotype.

Answer 3

Genetic anticipation is defined as follows:

As TNRs expand with SUBSEQUENT GENERATIONS, the disease presents at an EARLIER age, and demonstrates an INCREASINGLY SEVERE clinical phenotype.

Question 4

Huntington’s symptoms and mode of inheritance, including mutation

How to diagnose?

Answer 4

Saccadic extraocular eye movements
Hypertonia in all extremities
Wide-based and ataxic gait
Involuntary choreiform movements
Cognitive impairment
Mood disorders
Midlife onset

Protein aggregates modify transcription, induce proteolysis, interfere with axonal transport, and disrupt synaptic transmission.

AD

Increased CAG in first EXON of huntingtin protein (CODING MUTATION)

Paternal transmission because repeat expansion occurs through spermatogenesis

Disease phenotype must have more than 39 repeats.
Premutation is between 36-39 repeats, with incomplete penetrance.

Can diagnose via PCR to detect size of TNR expansion.

Question 5

Fragile-X Syndrome:

Inheritance Pattern

Symptoms

Location of mutation

Facts about premutation form

Affected protein and what it does, and what happens when it’s mutated

Answer 5

X-linked, maternal expansion (which occurs in OOCYTE)

Long, narrow face, prominent forehead and jaw, large everted ears, hyperextensibility of joints, macroochidism, intelelctual diability, Autism

Mutated in promoter (5’ UTR) of FMR1 gene, needs more than 200 repeats for full mutation.

Premutation is 55-200 repeats, and can cause Tremor-Ataxia syndrome (seen more in males) which is a progressive neurodegenerative disorder, with late onset cerebellar ataxia. Can also cause Primary Ovarian Insufficiency. Premutation results in sequestration of RNA-BPs from other transcripts, which causes the above phenotypes.

FMR1 is an RNA-BP that’s a translational regulator of target mRNAs. When it’s mutated, gene gets METHYLATED,there is TRANSCRIPTIONAL SILENCEING of FMR1 gene and absence of FMR protein.

Question 6

Friedrich’s Ataxia:

Mode of inheritance

Location of mutation, which gene affected

Which tissues is this protein usually found in?

Clinical triad of FA?

Anticipation or no anticipation?

Specific symptoms?

Answer 6

AR

First intron of Frataxin gene (found in mito), which causes diminished protein expression because of faulty splicing.

Sensory cells of DRG, cardiomyocytes, pancreatic beta cells

Triad: Neurologic dysfunction, cardiomyopathy with palpitations and CHF, diabetes mellitus

Anticipation

Ataxic gait–> weakness in extremities, dysarthria, dysphagia
COGNITIVE FUNCTION IS USUALLY PRESERVED IN FA

Question 7

Myotonic Dystrophy Type I

Mode of inheritance/expansion

Where is the mutation?

How many repeats until full mutation?

Symptoms

Mechanism that explains the TNR expansion in this disease?

Answer 7

AD, usually inherited from mother, because males will not transmit more than 1000 repeats.

3’UTR of DMPK gene

At least 50

Mild= cataracts and mild myotonia
Classic= muscle wasting and weakness, myotonia, cataracts, balding, cardiac conduction defects
Severe (congenital) = infantile hypotonia, respiratory dysfunction, cognitive impairment

Splicing factors are sequestered by the additional repeats, causing RNA-mediated toxicity (decreased RNA stability, altered protein conformation, and differential RNA distribution)

Question 8

Imprinting is ____ in primordial germ cells, while the imprinting _____ in somatic cells. Imprinting is ______ in gamete formation.

Answer 8

Imprinting is ERASED in primordial germ cells, while the imprinting is MAINTAINED in somatic cells. Imprinting is RE-ESTABLISHED in gamete formation.

Question 9

Prader-Willi Syndrome

• most common form of _____
• caused by ______ deletion of ______ or _____ uniparental disomy because the region covers a lot of ________ genes.

Clinical features: ______, ______, _____, ______, _____
-Early onset

Answer 9

Prader-Willi Syndrome

• most common form of SYNDROMIC OBESITY
• caused by PATERNAL deletion of 15-Q REGION or MATERNAL uniparental disomy because the region covers a lot of MATERNALLY-IMPRINTED genes.

Clinical features: HYPOTONIA AT BIRTH, GENITAL HYPOPLASIA, MILD-MODERATE COGNITIVE IMPAIRMENT, HYPERPHAGIA, SHORT STATURE
-Early onset

Question 10

Angelman Syndrome is a ______ disorder

Caused mostly by _____ deletion of _____, which is a region that covers a lot of _____-imprinted genes, then caused by _____ uniparental disomy

Symptoms: ______, ______, ______

Answer 10

Angelman Syndrome is a NEURODEVELOPMENTAL disorder

Caused mostly by MATERNAL deletion of 15Q11, which is a region that covers a lot of PARENTALLY-imprinted genes, then caused by PATERNAL uniparental disomy

Symptoms: SEVERE INTELLECTUAL DISABILITY, HAPPY DEMEANOR, NON-VERBAL