FRAX Flashcards
Genetic mutation
Trinucleotide repeat expansion CGG tract in the 5’UTR of the FMR1 gene
Gene deletions and point mutations within the RNA binding domain account for small number of cases
Incidence
1 in 4000-5000 males
Most common single gene cause of LD
Most common cause of autism
The CGG repeat
Highly polymorphic in population 5-58 repeats
Interspersed with AGG interruptions, thought to confer stability
Expansion to full mutation only occurs by maternal transmission
Mosaicism
15-20%
2 forms:
- Repeat size mosaicism ( full and premutation in males)
- Methylation mosaicism (full mutations variably methylated, milder phenotype)
Tissue mosaicism?
Phenotype
ID Social and behavioural problems Autism Subtle physical features: -Large ears -Elongated face -Macroorchidism -Joint hyper mobility -Hypotonia
Pathogenicity of FXS
Expansion to full mutation causes hypermethylation of gene promoter and gene silencing
Methylation of CGG cytosines
Deacetylation of tails of his tones H3 and H4
Reduced methylation of lysine 4 (H3K4)
Increased methylation lysine 9 (H3K9)
Results in heterochromatin configuration to exclude TF binding
Role of FMRP
Expressed predominately in brain (differentiated neurons in hippocampus and granular layer of cerebellum) and testes
Role in down regulation of translation of specific target mRNAs
In mice binds and stabilises PSD-95 mRNA (regulates neuronal synaptic signalling and learning)
20 isoforms by alternative splicing
FXTAS
Fragile X associated tremor/ataxia syndrome
FXTAS pathogenicity
Premutation trinucleotide repeat expansion in FMR1 gene
Increase in gene transcription and reduced translation results in accumulation of FMR1 mRNA, which contributes to nuclear inclusions
Toxic gain of function effect
Translation of other proteins impaired due to increased interaction of trinucleotide binding proteins and translation factors with inclusions, impairing translation of proteins involved in fundamental cellular processes (model)
Brain atrophy
FXTAS phenotype
Late onset Age of onset and severity correlate with CGG repeat length Progressive intentional tremor Parkinsonism Ataxia May progress to dementia Peripheral neuropathy
Males and Females (females lower risk)
1/3 males with PM affected
5% men with sporadic ataxia may have FXTAS
FXPOI
Fragile X associated primary ovarian insufficiency
FXPOI phenotype
Amenorrhea before age 40 for 4 or more months
Varying degree of ovarian function
Elevated FSH within menopausal range
5-10% with FXPOI can conceive
FXPOI pathophysiology
Carriers of FMR1 premutation (20% affected compared to 1% pop)
Risk increased for repeat lengths 80-100
Molecular mechanism unknown
May be due to over production of mRNA
Other causes of POI
Turner syndrome
X Chr rearrangements
Chemotherapy
What proportion of women with POI have a FMR1 premutation?
6.5%
FMR1 testing referral reasons
Diagnosis/exclusion with presenting symptoms of FXS FTAS or FXPOI
Carrier testing for FH
Prenatal
Prenatal diagnosis
Females with premutation or full mutation
Amplified CGG PCR on amino or CVS
Urgent TAT 3 days
Test for MCC
Methylation pattern may not be representative (20% CVS DNA partially or unmethylated)
Describe the different repeat classes and associated phenotype
under 45 (Normal)
45-54 (Intermediate)
55-200 (Premutation) Risk of FXTAS or FXPOI (females)
over 200 (Full mutation) Males affected, females variable (~50% affected with milder phenotype)
Molecular pathogenesis FXS
Reduction in FMRP
Thought to have role in down-regulation of translation of target mRNAs by forming part of a messenger ribonucleoprotein complex that in turn interacts with members of the RNA-induced silencing complex and ribosomes to regulate translation in neurons
