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CASE FILES: BIOCHEMISTRY
Many forms of fragile X syndrome are examples of insertions in multi-
ples of three where the outcome is detrimental not because of altered amino
acid sequence but rather a loss of protein expression. Deletions and inser-
tions typically occur in highly repetitive sequences, and this is exactly what
is seen in fragile X. Fragile X syndrome is the most common form of
inherited mental retardation. It affects approximately 1 in 4000 males and
1 in 8000 females. Mutations of the X chromosome, including fragile X, may
account for the higher number of male patients in mentally handicapped facil-
ities. The fragile X mental retardation 1
(FMR1)
gene is highly conserved.
Normal individuals have 7 to 60 (CGG) repeats in the 5'-untranslated
region, and the repeats are often broken up by AGG. Many fragile X indi-
viduals have an increase in the number of CGG repeats, which may
expand to over 230 repeats. This is termed the
full mutation.
Repeats rang-
ing from 60 to 230 are called a premutation. The premutation carrier has nor-
mal fragile X mental retardation protein (FMRP) levels, but the gene is
unstable in its passage to offspring.
The fragile X phenotype is mainly caused by the loss of FMRP resulting
from CGG trinucleotide repeat expansion of the
FMR1
gene. However,
some point mutations and deletions in the
FMR1
gene show the same pheno-
type as the repeat expansion. The alteration arising from the trinucleotide
repeat expansion within the promoter region of
FMR1
leads to enhanced local
methylation and ultimately transcriptional silencing. DNA methylation causes
protrusions in the DNA helix where the methylated cytosines interfere with
transcription factor binding. This is a common property used for gene regula-
tion. However, in the case of fragile X, the methylation signals to halt all
expression of FMRP. Loss of FMRP gives the phenotypical characteristics
commonly seen in fragile X patients.
C O M P R E H E N SIO N Q U E ST IO N S
[13.1] A 6-year-old boy visits his physician because his parents have noticed
autistic behavior and speech problems. The mother’s family does have
a history of mental retardation. Therefore, the physician suggested a
genetic screen of the fragile X mental retardation 1
(FMR1)
gene for
fragile X syndrome. Polymerase chain reaction (PCR) revealed borderline
fragile X syndrome.
What situation most likely explains this result?
A. A complete loss of fragile X mental retardation protein (FMRP)
B. An
FMR1
gene CGG repeat expansion of 60 with partial DNA
methylation
C. An
FMR1
gene CGG repeat expansion of 230 with minor DNA
methylation
D. An
FMR1
gene CGG repeat expansion of 280 with complete DNA
methylation
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