2. Sd. X- fragil se manifesta cu precadere la barbati printr-un retard mental
grav
3. Sindromul X- fragil
Se datorează unei mutaţii 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 baieţii cu o astfel de amplificare, unde codonul CGG este deci supranumerar,
apare un retard psihomotor grav.
Sindromul X-fragil este cea mai cunoscuta cauza de autism
4. 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,
urechi mari si
proeminente, maxilare
proeminente
6. 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 de cresterea sintezei de FMR1.
7. 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
raspunsul de mai jos.
Interpretati desenul alaturat, apoi rasturnati
de agaroza.
mai mare, cu atat mai greu se va deplasa in gelul
de la minus la +; cu cat fragmentul de ADN este
In analiza Southern blot alaturata ADNul migreaza
8. Numarul de repetitii ale Situs fragil
codonului detectabil Inteligenta Descendenti
(CGG) (citogenetic)
Barbati cu 50-200 repetitii Nu Normala Fete purtatoare (PM)
(premutatie =“PM”) (barbat purtator) Baieti normali (fara PM)
Barbati cu 200-2000 repetitii Da Retard moderat Fete purtatoare (M)
(mutatie completa=“M”) pana la sever Baieti normali (fara PM)
Femei cu 50-200 repetiţii Nu Normala Baieti bolnavi (M)
(premutatie) Fete normale (fara PM)
sau purtatoare (PM)
Femei cu 200-2000 repetiţii Da De la normal Baieti bolnavi (M)
(mutatie completa) retard moderat Fete normale (fara PM)
sau cu M
9. Femeile cu sindromul X-fragil
• 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.
10. 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
11. 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) iar altii X-lincata recesiva (http://www.genetics.edu.au/pdf/factsheets/fs42.pdf)
Poate cel mai corect este sa se adopte parerea ca, bolile determinate de gene de pe
cz. X sunt “doar” X-lincate, cum propunea deja in 2004 Dobyns de la Universitatea
Illinois din Chicago (Am J Med Genet A. 2004 Aug 30;129A(2):136-43.Inheritance of most X-linked traits is not dominant or recessive, just X-linked.)
12. 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!
14. Pentru cine nu se asaza doar pe carti, cateva date suplimentare in continuare, dar in original
15. FMR1 gene
contains 17
exons
spanning 38
kb.
http://bioquest.org/icbl/icbl_details.php?product_id=3783
16. FMRP - The highest levels were observed in neurons, while glial cells contained very low levels.
17. 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-4-isoxazole 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 RNA-induced silencing complex (RISC). FMRP is transported to dendritic spines,
together with its associated RNAs and proteins. mRNP, messenger ribonucleoprotein particle;
NES, nuclear export signal; NMDA, N-methyl-D-aspartate; NLS, nuclear localization signal
• http://www.nature.com/nrg/journal/v6/n10/full/nrg1691.html
19. 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 (YB1)). miRNA, microRNA; ncRNA,
non-coding RNA.
20.
21. 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-hydroxy-5-
methyl-4-isoxazole propionic acid) and NMDA (N-methyl-D-aspartate)) receptor
internalization (INT.) during hippocampal long-term depression, which could lead to fewer
receptors being present on the postsynaptic membrane and to thinner spines. mGluR,
metabotropic glutamate receptor
22. 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 immature morphology (lower right).
article: From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome
Claudia Bagni & William T. Greenough in Nature Reviews Neuroscience 6, 376-387 (May 2005
23. 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
non-coding RNA brain cytoplasmic RNA 1 (BC1) (c) or microRNAs (miRNAs) (d).
eIF2C2, eukaryotic translation initiation factor 2C, 2
25. • 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
• Exceptional ,exista persoane cu > 200 repetitii CGG, dar la care gena FMR1 nu este
metilata. Gama de simptome este foarte larga in astfel de cazuri, iar caracteristicile
sindromului X-fra sunt mult mai putin severe.
26. Pentru cei care au reusit sa ajunga sa citeasca tot pana la sfarsit (adica aici) de curs:
