Sindromul X- fragil

(Sindromul Martin-Bell)

Sd. X- fragil se manifesta cu precadere la barbati printr-un

retard mental grav

Sindromul X- fragil
Se datoreaz unei mutaii dinamice ( = din generatie in generatie
numarul de repetitii trinucleotidice poate creste )
In gametogeneza materna (cu precadere) are loc amplificarea
secventei de 3 baze azotate [codon].
Denumirea este data de faptul ca initial, prin analiza citogenetica
cromozomul X parea sa prezinte o ruptura la nivelul telomerului
bratului q, adica s-a presupus existenta la acest nivel a unui
situs fragil (zona cz. cu rupturi frecvente)
Astazi, se stie ca, aspectul citogenetic este datorat multiplicarii
excesive a codonului CGG la nivelul promotorului genei
FMR1(Fragile X Mental Retardation)
La baieii cu o astfel de amplificare, unde codonul CGG este deci

Situsul fragil,
indicat prin sageti
in imaginea
alaturata (d), este
de fapt, un codon
amplificat anormal

DISMORFISMUL
CRANIO-FACIAL
este evident:
macrocefalie, fata
alungita, frunte
lunga si
proeminenta,

Diagnosticul clinic
este certificat prin
analize moleculare,
ce evidentiaza
prezenta
repetitiilor
trinucleotidice.

Tabloul clinic al sindromului asociaza retardul

mental de la moderat la sever, macroorhidia
(postpubertara, cu testicule avand volumul >
40ml) si dismorfismul cranio-facial specific.

http://www.nfxf.org/html/facial.htm

In majoritatea cazurilor sindromul este cauzat de expansiunea

trinucleotidica instabila CGG de la nivelul genei FMR1 si
metilarea anormala, care produce supresia transcriptiei si
consecutiv nivele scazute ale proteinei FMRP la nivel cerebral.
Sindromul X- fragil determina aproape o jumatate din cazurile de retard
mental si este ca frecventa a doua cauza de handicap psihic dupa
sindromul Down.
In OMIM pe langa sd. X-fragil, apare ca entitate de sine-statatoare si
FXTAS (fragile X tremor/ataxia syndrome) produs de o premutatie urmata

Interpretare: I1 prezinta premutatia (pe

singurul sau cz. X), pe care fiica sa, II2, o
mosteneste de aceeasi marime;II2 are 2 cz. X
deci unul cu premutatia de la tata si unul cu
gena FMR1 normala, mostenit de la mama,
care nu mai este reprezentata in arborele
genealogic; III1 are mutatia completa, adica
sd. X-fragil, amprenta ADNului sau aproape ca
nu s-a deplasat de la punctul de start. II1 are
un cz. X cu gena normala

rasturnati raspunsul de mai jos.

Interpretati desenul alaturat, apoi

agaroza.
atat mai greu se va deplasa in gelul de
fragmentul de ADN este mai mare, cu
migreaza de la minus la +; cu cat
In analiza Southern blot alaturata ADNul

Numarul de repetitii ale

Situs fragil

codonului

detectabil

(CGG)

(citogenetic)

Barbati cu 50-200 repetitii

Nu

(premutatie =PM)
Barbati cu 200-2000 repetitii

Da

(mutatie completa=M)
Femei cu 50-200 repetiii

Nu

Inteligenta

Descendenti

Normala

Fete purtatoare (PM)

(barbat purtator)

Baieti normali (fara PM)

Retard moderat

Fete purtatoare (M)

pana la sever

Baieti normali (fara PM)

Normala

Baieti bolnavi (M)

(premutatie)

Fete normale (fara PM)

sau purtatoare (PM)

Femei cu 200-2000 repetiii

(mutatie completa)

Da

De la normal

Baieti bolnavi (M)

retard moderat

Fete normale (fara PM)

sau cu M

Femeile cu sindromul Xfragil

Femeile purtatoare de premutatie pot prezenta:

insuficienta ovariana, menopauza instalandu-se inainte de varsta de 40 de

ani,
menopauza prematura, instalata inainte de varsta de 45 de ani sau
o disfunctie ovariana ( fertilitate redusa) in general

Scaderea fertilitatii este corelata cu cresterea de FSH si alte

modificari hormonale.

Femeile purtatoare ale mutatiei complete nu au riscurile de mai

sus. Marimea mutatiei nu se coreleaza cu gravitatea clinica
datorita inactivarii cz.X (cromatina sexuala)

Sfatul genetic dupa o testare prenatala pozitiva nu poate

prezice cu fidelitate afectarea intelectuala, comportamentala sau
psihologica in cazul fetelor cu mutatia completa. Tulburarile se
manifesta de la foarte usoare pana la retard sever si autism.

Se observa caracteristica acestui tip particular de transmitere si anume

BARBATII PURTATORI (I3, IV 1 si IV2). Acestia au premutatia si deci boala
nu se manifesta la intensitatea maxima, adica nu au un retard mental
grav

La fel cum transmiterea acestui sindrom este particulara. Cu

siguranta este o transmitere X-lincata, gena FMR1 fiind pe cz. X.
Unii autori considera transmiterea X-lincata dominanta
(http://ghr.nlm.nih.gov/condition/fragile-x-syndrome)
(http://www.genetics.edu.au/pdf/factsheets/fs42.pd

iar altii X-lincata recesiva

f)

Poate cel mai corect este sa se adopte parerea ca, bolile

determinate de gene de pe cz. X sunt doar X-lincate, cum

In acest arbore genealogic este specificat numarul de repetitii

trinucleotidice ale fiecarei persoane. Pe langa prezenta femeilor
si barbatilor purtatori de PM, un caz special il reprezinta IV5 , care
are mutatia completa, dar nu este bolnava!

Urmatoarele sindroame sunt cele mai frecvent intalnite boli

cauzate de mutatii dinamice.

u cine nu se asaza doar pe carti, cateva date suplimentare in continuare, dar in o

FMR1 gene
contains 17
exons
spanning 38
kb.

p://bioquest.org/icbl/icbl_details.php?product_id=3783

FMRP - The highest levels were observed in neurons, while glial cells containe
low levels.

Text la imag anterioara

Expansion of CGG repeats in the fragile X mental retardation 1 (FMR1)

gene that encodes FMRP underlies fragile X syndrome (FRAXA). Repeats
that contain >200 copies (full mutation) lead to loss of FMRP expression.
FMRP contains two domains that bind RNA: the KH2 domain and the RGG
box. The Ile304Asn mutation in the KH2 domain, which prevents FMRP from
binding targets that contain the kissing complex motif, gives rise to a
severe mental retardation phenotype.a| Abnormal dendritic spine
morphology in patients with FRAXA. An increased density of long, immature
dendritic spines indicates that FMRP has a role in synaptic maturation and
pruning, possibly through its regulation of gene products that are involved
in synaptic development. FMRP might also have a regulatory role in
activity-dependent translation at the synapse. Stimulation of postsynaptic
metabotropic glutamate receptors (mGluRs) results in increased protein
synthesis and subsequent internalization of-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) receptors, which is important in the
expression of long-term depression. FMRP, which is also upregulated by
mGluRs, serves to dampen this process. The absence of FMRP in FRAXA
results in over-amplification of this response.b| FMRP modulates the
translation of its targets, probably through its association with the RNAinduced silencing complex (RISC). FMRP is transported to dendritic spines,
together with its associated RNAs and proteins. mRNP, messenger

http://www.nature.com/nrn/journal/v6/n5/fig_tab/nrn1667_F1.html

Text la imag. ant

Fragile X mental retardation protein (FMRP) enters the

nucleus and could function through two possible
mechanisms. In the first (1), FMRP could interact with other
proteins, with itself (for example, the FMRP-homologous
proteins FXR1P and FXR2P), and with RNA/mRNA to form a
ribonucleocomplex that is probably involved in mRNA
export from the nucleus to the cytoplasm. Once in the
cytoplasm, a 'core' complex, containing FMRP and some of
its nuclear partners, would interact with cytoplasm-specific
proteins (such as cytoplasmic FMRP-interacting protein 1
(CYFIP1), CYFIP2 and Staufen) and move along dendrites to
the synapses, transporting RNA/mRNA and, later, regulating
synaptic protein synthesis. In the second mechanism (2),
FMRP could be involved in the nuclear RNA interference
pathway that is associated with small, non-coding RNAs
(short hairpin RNAs or shRNAs) and specific nuclear
partners (that is, nucleolin and Y-box binding protein 1

Text la imag. ant

At synapses, protein synthesis is initiated by different cellular stimuli, and

this leads to an independent response of a single synapse that can
influence synaptic plasticity. a | In a wild-type spine, stimulation of
metabotropic glutamate receptors enhances the synthesis of fragile X
mental retardation protein (FMRP), which could act to negatively regulate
the translation of proteins that are involved in ionotropic receptor
internalization during long-term depression and of proteins that regulate
the cytoskeleton (such as microtubule-associated protein 1B (MAP1B),
activity-regulated cytoskeletal-associated protein (ARC), arginine-binding
protein 2 (ARGBP2), postsynaptic density protein 95 (PSD-95) and Rac1).
This receptor-coupled signalling pathway might also be responsible for
FMRP phosphorylation and the consequent release of mRNAs from
translational inhibition and/or the activation of translation of other specific
dendritic mRNAs. The correct balance between synthesis and degradation
of these proteins would promote and maintain the mature shape of the
synapse. b | In a spine of a patient with fragile X syndrome, or in the
mouse model of the syndrome, the absence of FMRP would lead to an
increase and/or decrease in the translation of protein regulators of the
cytoskeleton, both of which might have an effect on the lengthening of
dendritic spines. c | The absence of FMRP could also lead to an increase in
the translation of proteins that are involved in ionotropic (AMPA (-amino-3-

The figure shows a hypothetical mechanism through which the absence of fragile X
mental retardation protein (FMRP) could lead to failure of synapse pruning and, as
a consequence, dendrite pruning, in a typical spiny stellate neuron in a whisker
barrel (centre). The model assumes that FMRP regulates the synthesis of structural
proteins (for example, postsynaptic density protein 95 (PSD-95)) or signalling
proteins that form part of a complex that is important for stabilizing and maturing
developing synapses (see Fig. 4 for one possible conceptualization of this process).
When FMRP is present, this stabilization complex (carried by the transport granule)
is selectively targeted to active synapses (upper left), which results in selective
maturation and stabilization of spines (upper right) and pruning of non-stabilized
synapses. In the absence of FMRP (lower left), the stabilization complex is equally
targeted to active and inactive synapses, which results in a weaker form of
maturation and stabilization, and gives rise to greater numbers of synapses and an

Fragile X mental retardation protein (FMRP) binds different

neuronal mRNAs. Four mechanisms of target recognition have
been characterized. FMRP could recognize a G-quartet structure
(a) or a poly(U) stretch (b) in the mRNA. Alternatively, FMRP
could bind indirectly to the mRNA through either the small noncoding RNA brain cytoplasmic RNA 1 (BC1) (c) or microRNAs
(miRNAs) (d). eIF2C2, eukaryotic translation initiation factor 2C, 2

In loc de tratament al sd. X

Factorul major care determina prezenta sau absenta sindromului

X-fragil este numarul de repetitii CGG in gena FMR1 de pe
Xq27.3.

In mod tipic, numarul de repetitii > 200, declanseaza metilarea

insulelor CpG din regiunea promotor a genei.

Ca urmare, productia de FMRP(fragile X mental retardation

protein) este oprita. Absenta proteinei are ca rezultat aparitia
sindromului X-fra

Totusi, exista si cazuri, ce nu se incadreaza nici in premutatii si nici in

mutatii complete. Un exemplu este mozaicul, celulele avand grade
diferite de metilare urmare a unui numar variat de repetii
CGG.Impactul bolii depinde in astfel de cazuri de procentul de celule
care sunt afectate si de tipul de tesut implicat

Pentru cei care au reusit sa ajunga sa citeasca tot pana la sfarsit (adica aici) de