Triplet Repeats FraX Flashcards
What is the mode of inheritance of FraX?
X-linked dominant manner with variable penetrance
What is the gene and where is it located, and the protein involved in FraX?
The fragile X mental retardation 1 (FMR1) gene is located on Xq27.3 and provides instructions for making an RNA binding protein called fragile X mental retardation 1 protein (FMRP).
What is the function of FMRP
FMRP regulates the production of other proteins and plays a role in the development of synapses. FMRP is thought to act as a shuttle within cells by transporting messenger RNA (mRNA) from the nucleus to areas of the cell where proteins are assembled. FMRP also helps to control when the instructions in these mRNA molecules are used to build proteins.
What is the triplet repeat involved in FraX?
CGG repeat in 5’UTR.
what is the pathogenic mechanism in FraX?
Aberrant methylation of a CpG island 250 base pairs downstream of the CGG repeat causes Fragile X syndrome in (male) patients when the CGG tract expands to over 200 repeats.
What level of FMR1 mRNA have been found in premutation carriers?
Premutation carriers have been found to have higher levels of FMR1 mRNA and normal levels of FMRP.
What is the mechanism for POF and FXTAS?
Excess of FMR1 mRNA could be responsible for a toxic gain of function phenotype resulting in FXTAS and POI. They have a different pathogenic basis to Fragile X syndrome, probably due to subtle reductions in FMRP levels or to RNA gain-of-function effects.
What are the clinical features of FraX?
Moderate to severe intellectual and social impairment, characteristic appearance (large head, long face, large ears, prominent forehead and chin, protruding ears), joint laxity and macro-orchidism.
Where is the fragile site?
• A fragile site (FRAXA) is expressible at the gene locus at Xq27.3 in around 2-40% of blood cells in affected males.
What is the result of a full mutation on the protein?
• Full mutations (>200 repeats) result in hypermethylation of the DNA in and around the CGG tract, curtailed gene expression and no FMRP production.
What is FRAXE?
FRAXE is a separate condition caused by mutations in FMR2 located distal to FMR1. Large expansions of GCC in 5’ UTR, considerably less severe phenotype.
What are the repeat size ranges for FraX?
Normal 6 to 50 repeats
Intermediate 46-58 (under 50 likely to be stable, 50-58 may show instability).
Premutations: from approximately 55 to 200 repeats which are unmethylated on active X chromosomes but are subject to X-inactivation in females.
Full mutations: From approximately 200 to 1000 repeats or more as well as methylation of the DNA in and around the expanded repeat tract, even on the active X chromosome.
More information on intermediate alleles?
Represent the overlap zone between stable normal alleles and unstable premutations. Often transmitted stably but are more likely to show unstable transmission with increasing size, usually by only one or two repeats.
• The stability of transmissions can vary within a family.
• It is not known whether any alleles in the intermediate range show clinical involvement in abnormal phenotypes such as POI, FXTAS or developmental delay.
• The stability of an intermediate allele appears to correlate with the presence of two or more interspersed AGG motifs within the CGG tract.
• Most normal and intermediate alleles consist of (CGG)¬9 or 10AGG(CGG)9AGG(CGG)n, the distal tract of CGG accounting for most of the length variation between alleles.
• Since unstable premutations are usually pure CGG repeats or contain only a proximal AGG interspersion, it is assumed that the loss of one or both AGG motifs or their conversion to CGG in an intermediate allele would predispose it to instability.
More info on premutations?
It is recommended that all patients with a high prior risk or a confirmed family history of fragile X be tested by southern blotting as well as by PCR.
The distinction between a premutation and a full mutation is more likely due to methylation status rather than the exact size of the allele and so a methylation-sensitive enzyme is combined with another enzyme to give a convenient size of fragment for resolution of the expansion and their methylation status.
• The probability of conversion to a full mutation on maternal transmission in a single generation is low for premutations of 59-70 repeats but rises to >90% for premutations of more than 90 repeats.
• Expansion to a full mutation only occurs when transmitted by a female.
More info on full mutations?
- Approximately 20% of full mutation patients also show some mosaicism for a premutation which may be the same size (methylation mosaic) but is usually smaller than the full mutation. Some patients are methylation mosaic, in which full mutations have varying degrees of methylation.
- Almost always, extensive somatic variation of repeat number is observed in a peripheral blood sample of a patient with a full mutation.
- The southern blot double digest detects most expansions but may have limits to its sensitivity in cases of full mutations which appear as diffuse smears due to somatic mosaicism (particularly in females, where the presence of the normal allele may draw attention away from any faint expanded fragments).
- Extreme skewing of X-inactivation in favour of the mutant allele may result in small premutations being hard to detect in females.
