MOLECULAR GENETICS MONOGRAPH

MENDELIAN INHERITED CONDITIONS

JONATHAN MILHOMENS


The fragile X syndrome and its main characteristics

Fragile X syndrome (FXS) is an X-linked inherited mental disorder, caused by a mutation
in the FMR1 gene. The FXS is the most common form of inherited mental retardation in humans.
It is believed that 20% of the general population with an intelligence quotient (IQ) below what is
considered normal (IQ < 70) has an X-linked mental retardation, between those, the locus
responsible for the fragile X syndrome shares the largest amount (GARBER, K. B. et. al., 2008;
PENAGARIKANO, O. et. al., 2007).
The first description of X-linked mental retardation came in 1943 by Martin and Bell. In
1969 Herbert Lubs developed a chromosomal test for the unusual constrictions in the end of the
long arms of the X chromosome that he found in 7 individuals of the same family. Sometime later,
the so called Martin-Bell syndrome or marker X syndrome, became known as fragile X syndrome,
after Richards and Sutherland analyzed and associated the descriptions from Martin-Bell and
Lubs with FXS (PENAGARIKANO, O. et. al., 2007).
The prevalence of this syndrome in the general Caucasian population is approximately 1
in 4000 for males and 1 in 8000 for females, for other populations little is known about the
prevalence or the incidence of FXS. In one population-based study for non-Caucasians, the result
for African-Caribbean and African- American populations showed a higher estimate point than in
Caucasians, such as 1 in 2500 for the general population, but further studies are needed to
investigate this results (CRAWFORD, D. C. et. al., 2001).
The primarily characteristics and clinical indications of FXS is often slow developmental
hallmarks, such as mild motor and language, autistic-like behaviors, low IQ and some common
observable features such as prominent ears and fore-heads, long narrow faces and long palpebral
fissures. In general, the mental deficits include short-term memory problems, logical and
visuospatial inabilities. Since it is an X-linked disorder, females are much less affected than males,
mostly in terms of cognitive ability. Full-mutation females often shows a normal IQ (GARBER, K.
B. et. al., 2008).
The mutation that leads to FXS is a CGG polymorphic repeat at the 5 untranslated region
(UTR) of the FMR1 gene, located at Xq27.3. The repeat expansion length of CGG determines
the how the individual is affected. Normal individuals have 6 to 54 polymorphic copies, female
carriers and normal transmitting males (NTMs) bears 55 to 200 repeats (categorized as a pre-
mutation) and when the expansion is larger than 200 repeats, it is considered as a full-mutation
and the individual might present features of mental retardation and other phenotype
characteristics. The mutation is passed between generations, were a NTM does not transmit the
gene to his male offspring but to his female daughter, and the mother can transmit both to his son
or daughter, and the mutation might be given with expansion, increasing exponentially according
to the number of repeats from the mothers allele. Full-mutation expansion only occurs when
transmitted by a female carrier, once the full-mutation males only carries pre-mutation alleles in
their sperm. When carrying the full-mutation, the gene sequence becomes abnormally methylated
and the gene is silenced. The absence of the FMR1 gene protein must be the cause of the mental
retardation, since it is a single gene based syndrome (JIN, P.; WARREN, S. T., 2000;
PENAGARIKANO, O. et. al., 2007; SHERMAN, S. et. al., 2008).
To understand how the FMRP causes mental retardation, this protein has been
extensively studied in the past several years. The main phenotype of fragile X syndrome, mental
retardation, is in the Central Nervous System (CNS), the question is: What is the function of FMRP
is in CNS, and how its absence leads to mental deficit? Based on the findings from the last
decade, it has been speculate that FMRP plays a role in the transportation of mRNAs from
nucleus to cytoplasm in neurons (crucially in dendrites), and also regulates the protein synthesis
at that local, by being part of polyribosome complexes. The regulation of protein synthesis in the
dendrites allows synaptic development and plasticity, seeing that synaptic plasticity is essential
for promotion of memory and learning processes, the last observations on the physiological role
of FMRP explains how the mutation generates the syndrome (penagakioke Crawford, outros).
The molecular mechanism for the trinucleotide repeat expansion is still unclear. It is believed that
this phenomenon is likely due to a mechanism of slipping-strand mispairing during DNA
replication in the Okazaki fragments (PENAGARIKANO, O. et. al., 2007).





REFERENCES

Crawford, D. C. et. al. FMR1 and the fragile syndrome: Human genome
epidemiology review. Genetics in Medicine. Vol. 3, n. 5, pg. 359-371, 2001.
Garber, K. B. et. al. Fragile X syndrome. Nature and European Journal of
Human Genetics. N. 16, pg. 666-672, 2008.
Jin, P.; Warren, S. T. Understanding the molecular basis of fragile X
syndrome. Human Molecular Genetics. Vol. 9, n. 6, pg. 901-908, 2000.
Penagarikano, O. et. al. The pathophysiology of Fragile X Syndrome. Annual
Review of Genomics and Human Genetics. N. 8, pg. 109-129, 2007.
Sherman, S. et. al. Fragile X syndrome: Diagnostic and carrier testing.
Genetics in Medicine. Vol. 7, n. 8, pg. 584-587, 2008.