The Principles of Clinical Cytogenetics - Extra Materials - Springer

Fragile X 501
(KH domains) and clusters of arginine and glycine residues (RGG boxes), features typical of RNAbinding
proteins (74,77). Second, FMRP contains both a nuclear localization signal and a nuclear
export signal (78). FMRP is primarily a cytosolic protein, but its presence in the nucleus has been
reported by nuclear staining experiments (66,79). Furthermore, FMRP has been detected in the
nuclear pore (80). Taken together, current evidence suggests that FMRP shuttles between the nucleus
and the cytoplasm.
In addition, experimental evidence suggests that FMRP is involved in translational activities.
FMRP forms complexes with messenger ribonuclear particles (mRNP) and is associated with translating
ribosomes (78,81,82). Because RNP particles are formed in the nucleus, this observation further
supports the hypothesis that FMRP shuttles between the nucleus and the cytoplasm. Recent
experiments suggest that FMRP might play a role in regulation of translation for certain messages.
Laggerbauer et al. (83) demonstrated that FMRP suppresses translation by preventing the assembly
of the 80S subunit of the ribosome on the target RNAs. New evidence suggests that translational
control might be mediated through the RNA interference (RNAi) and/or micro-RNA (miRNA) pathways
(84,85).
The two major activities identified for FMRP, cytoplasm–nucleus shuttling and translational regulation,
imply that FMRP is a facilitator for the expression and localization of several messages and
proteins. The search for FMRP’s partners has identified at least seven such proteins, one of which
includes FMRP itself (71). In contrast, very few specific mRNAs that bind FMRP have been identified.
FMRP was shown to bind its own mRNA and also approximately 4% of fetal brain mRNAs
(74). Nearly a decade would pass before the identity of the specific mRNAs (other than the FMR1
transcript) binding to FMRP would be identified (86–88). These mRNAs contain a G-quartet structure,
a specific nucleic acid structure that facilitates binding to FMRP. Recent work also shows that
FMRP can be phosphorylated, a mechanism that possibly affects the binding of specific mRNAs
(89). Undoubtedly, research in the next decade will identify additional mRNA targets, whose roles
will be crucial for not only the understanding of the fragile X syndrome but other human behavioral
and cognitive disorders as well.
CLINICAL ASPECTS OF FRAGILE X SYNDROME
Full Mutation Phenotypes
Physical Phenotype
In males, the classic features of fragile X syndrome are X-linked mental retardation, macroorchidism,
and minor dysmorphic facial features including a long, oblong face with a large mandible
and large and/or prominent ears. At least 80% of affected males have one or more of these features,
but expression varies with age. Other frequent features are a high-arched palate, hyperextensible
finger joints, velvet-like skin, and flat feet. A small subgroup of males with a “Prader-Willi-like”
phenotype has been described by Fryns et al. (90). Heterozygous females express these same features
of fragile X syndrome, with manifestations being more common in females with mental disability
than in those of normal intelligence.
Behavioral Phenotype
The behavior of males with fraX, especially in childhood, is more consistent and diagnostic than
the physical features. They are typically hyperactive and delayed speech. Other complicating features
can include irritability, hypotonia, perseveration in speech and behavior, and autistic-like features
such as hand flapping, hand biting, and poor eye contact. Social anxiety and avoidance are
prominent features of fragile X syndrome in both sexes.
Recently, Hagerman (91) reviewed in detail the physical and behavioral phenotype of fragile X syndrome
(see also reference 92). The variability of expression makes clinical diagnosis difficult. Therefore,
fragile X syndrome should be considered in the differential diagnosis of all mentally retarded individuals.