14/01/2010

Progressive noradrenergic deficits in the locus coeruleus of Mecp2 deficient mice.

Publication date : december 2009
EuroRETT partners : Laurent Villard, Marseille.
Authors  : Roux JC, Panayotis N, Dura E, Villard L.
Link to the article : Journal of Neuroscience Research, 88:1500-1509.

Lay summary

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator. Mutations in this gene cause a wide range of neurological disorders. Mecp2 deficiency has been previously associated to catecholaminergic dysfunctions leading to autonomic defects in the brainstem and the sympathoadrenergic system of the mouse. The present study was undertaken to determine if the locus coeruleus (LC), the main noradrenergic cell group of the brain, is affected. The authors found several defects but no apoptotic neurons in the pons indicating that LC neurons are not dying but are more likely loosing their catecholaminergic phenotype. These results show a progressive catecholaminergic deficit in the LC of Mecp2 deficient null male mice could open new perspectives to better understand the autonomic and cognitive deficits due to the lack of Mecp2.

14/01/2010

Early postnatal behavioral changes in the Mecp2-308 truncation mouse model of Rett syndrome.

Publication date : november 2009
EuroRETT partners : Giovani Laviola, Roma.
Authors  : De Filippis B, Ricceri L, Laviola G.
Link to the article : Genes, Brain, Behav., 2010, 9:213-223.

Lay summary

In a mouse model of Rett syndrome (RTT) which expresses a truncated form of methyl-CpG-binding protein 2 (Mecp2) gene (Mecp2-308), we performed a neurobehavioral evaluation across the life span, starting from soon after birth till adulthood. A focus was made on those developmental phases and behavioral domains which have not been previously investigated. The results evidenced subtle anomalies on postnatal days (pnds) 3 to 9 (so-called presymptomatic phase) in spontaneous movements by hemizygous neonatal male mice. A significant decrease in ultrasonic vocalization rate, also emerged in Mecp2-308 pups. The same mice were also characterized by increased anxiety-like behaviors during the early symptomatic phase. Upon the clearly symptomatic stage, 5-month-old Mecp2-308 mice were also associated with motor coordination impairments. Present results provide an interesting timeline of the progression of symptoms in the Mecp2-308 model and emphasize the need for increased attention to the presymptomatic phase which may be especially informative in mouse models of human neurodevelopmental disorders. This analysis has provided evidence of precocious behavioral markers of RTT and has identified an early developmental window of opportunities on which potential therapies could be investigated.

14/01/2010

MECP2 is phosphorylated by HIPK2 and contributes to apoptosis.

Publication date : october 2009
EuroRETT partner : Charlotte Kilstrup-Nielsen, Busto Arsizio
Authors : Bracaglia G, Conca B, Bergo A, Rusconi L, Zhou Z, Greenberg ME, Landsberger N, Soddu S, Kilstrup-Nielsen C.
Link to the article : EMBO Reports, 2009, 10:1327-1333.

Lay summary
Mutations in the methyl-CpG-binding protein 2 (MeCP2) are associated with Rett syndrome and other neurological disorders. MeCP2 phosphorylation was shown to occur in the brain and modulate MeCP2 activity. However, the kinases directly responsible for this are largely unknown. Here, the authors identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it. HIPK2 modulates cell proliferation and apoptosis, and the neurological defects of Hipk2-null mice indicate its role in proper brain functions. These data reinforce the role of MeCP2 in regulating cell growth.

16/08/2010

Revisiting the phenotype associated with FOXG1 mutations : two novel cases of congenital Rett variant.

Publication date : october 2009
EuroRETT partner : Thierry Bienvenu, Paris.
Authors  : Bahi-Buisson N, Nectoux J, Girard B, Van Esch H, De Ravel T, Boddaert N, Plouin P, Rio M, Fichou Y, Chelly J, Bienvenu T.
Link to the article : Neurogenetics, 2010, 11:241-249.

Lay summary
The Forkhead box G1 (FOXG1) is a transcription factor that is critical for brain development. Recently, the FOXG1 gene was implicated in the molecular aetiology of the congenital variant of Rett syndrome. So far, 15 FOXG1 molecular alterations have been reported. The authors screened the FOXG1 gene in a cohort of 206 MECP2 and CDKL5 mutation negative patients (136 females and 70 males) with severe encephalopathy and microcephaly. The screening was negative in all males, but two de novo mutations (p.Y416X and p.E154GfsX300) were identified in two unrelated girls. Both patients showed neurological symptoms from the neonatal period with poor reactivity, hypotonia, and severe microcephaly. During the first year of life, both patients had feeding difficulties and made slow developmental progress. At 5 years old, the girls were significantly neurologically impaired with gross hypotonia, no language, convergent strabismus, and no voluntary hand use. Moreover, they presented a combination of jerky movements, hand-mouthing, and hand-washing stereotypies. Hence, FOXG1 mutation patients demonstrate severe encephalopathy compatible with the congenital variant, as well as additional features such as absent eye contact, inconsolable crying during the perinatal period, and delayed myelination with thin to hypoplastic corpus callosum. Although the overall frequency of mutations in FOXG1 in females with severe mental retardation and microcephaly appears to be low (1.5%), our findings suggest the requirement to investigate both point mutations and gene dosage in the FOXG1 gene in patients with severe encephalopathy with microcephaly and some Rett-like features.

11/12/2009

CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery.

Publication date : september 2009
EuroRETT partners : Vania Broccoli, Milano ; Nicoletta Landsberger, Busto Arsizio ; Thierry Bienvenu, Paris.
Authors  : Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V.
Link to the article : Human Molecular Genetics, 2009, 18:4590-4602.

Lay summary
Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause severe neurodevelopmental disorders including infantile spasms, encephalopathy, West-syndrome and an early-onset variant of Rett syndrome. CDKL5 is a kinase whose involvement in Rett syndrome can be inferred by its ability to directly bind and mediate phosphorylation of MeCP2.

In this paper, the authors report that CDKL5 localizes to specific nuclear structures in cell lines and tissues traditionally considered as storage/modification sites of pre-mRNA splicing factors. They provide evidence that CDKL5 is involved indirectly in pre-mRNA processing, by controlling splicing factor dynamics. These findings identify a biological process whose disregulation might affect neuronal maturation and activity in CDKL5 related disorders.

15/09/2009

Clinical diagnostic criteria for the early onset seizure variant of Rett syndrome

Publication date : april 2009
EuroRETT partners : Alessandra Renieri, Siena, Italy ; Alessandra Murgia, Padua, Italy.
Authors : Artuso R, Mencarelli MA, Polli R, Sartori S, Ariani F, Pollazzon Marozza A, Cilio MR, Specchio N, Vigevano F, Vecchi M, Boniver C, Bernardina BD, Parmeggiani A, Buoni S, Hayek G, Mari F, Renieri A, Murgia A.
Link to the article : Brain and Development, 2010, 32:17-24

Lay summary
Among Rett clinical variants, the early-onset seizure variant describes girls with early onset epilepsy and it is caused by mutations in CDKL5. In this paper, 9 cases were evaluated by two clinical geneticists, classified using a severity score system based on the evaluation of 22 different clinical signs and compared with 128 classic Rett and 25 Zappella variant MECP2-mutated patients, evaluated by the same clinical geneticists. Clinical features were compared with previously described CDKL5 mutated patients. All girls present epilepsy with onset varying from 10 days to 3months. Patients may present different type of seizures both at onset and during the whole course of the disease ; multiple seizure types may also occur in the same individual. After treatment with antiepileptic drugs patients may experience a short seizure-free period but epilepsy progressively relapses. Typical stereotypic hand movements severely affecting the ability to grasp are present. Psychomotor development is severely impaired. In the majority of cases head circumference is within the normal range both at birth and at the time of clinical examination. For the practical clinical approach, the authors propose to use six necessary and eight supportive diagnostic criteria.

21/04/2009

14q12 microdeletion syndrome and congenital variant of Rett syndrome.

Publication date : april 2009
EuroRETT partner : Alessandra Renieri, Siena, Italy.
Authors : Mencarelli MA, Kleefstra T, Katzaki E, Papa FT, Cohen M, Pfundt R, Ariani F, Meloni I, Mari F, Renieri A.
Link to the article : European Journal of Medical Genetics, 2009, 52:148-152.

Lay summary
Only two patients with chromosome 14q12 deletion have been reported to date. This article describes an additional patient with a similar deletion and improves the clinical delineation of this new microdeletion syndrome. It is characterized by a Rett-like clinical course with an almost normal development during the first months of life followed by a period of regression. A peculiar facial phenotype is also present. Interestingly, the FOXG1 gene is located in this region of human chromosome 14.

27/03/2009

Description of new mutations in CDKL5 and the associated phenotypes.

Publication date : > march 2009
EuroRETT partners : Silvia Russo, Milano ; Bruria Ben Zeev, Tel Hashomer
Authors : Russo S, Marchi M, Cogliati F, Bonati MT, Pintaudi M, Veneselli E, Saletti V, Balestrini M, Ben Zeev B, Larizza L.
Link to the article : Neurogenetics, 2009, 10:241-250.

Lay summary
CDKL5 mutations are responsible for a variant form of Rett syndrome with early-onset epilepsy and drug resistance. In 92 patients with different clinical presentations, 7 new mutations were identified. Six mutations were identified in "Rett-like" patients and 1 mutation in an "Angelman syndrome-like" patient. The clinical phenotype of the patients is described in that paper, showing that the more severe phenotypes are due to abnormal proteins rather than lack of protein.

11/02/2009

Gentamicin suppresses MECP2 nonsense mutations.

Publication date : february 2009
EuroRETT partner : Peter Huppke, Göttingen
Authors : Brendel C, Klahold E, Gärtner J, Huppke P.
Link to the article : Pediatric Research, 2009, 65:520-523.

Lay summary
Rett Syndrome (RTT) is caused in more than 60% of cases by nonsense (i.e. STOP) mutations in the MECP2 gene. Several molecules from the class of "aminoglycosides" can overcome these stops ("read-through") with an efficiency of up to 20%. This article reports that one such aminoglycoside called gentamicin, when given to MECP2 mutated cells in culture, is able to read-through MECP2 nonsense mutations with an efficiency of 6 to 21% (depending on the mutation) and to produce a normal size protein that is sent to the nucleus (like the normal MECP2 protein). It proves that this read-through strategy could be useful for Rett syndrome, although gentamicin itself would probably not be used because it is toxic and does not reach the brain easily.

11/02/2009

Tyrosine hydroxylase deficit in the peripheral nervous system of the « Rett mouse »

Publication date : december 2008
EuroRETT partner : Laurent Villard, Marseille
Authors : Roux JC, Dura E, Villard L.
Link to the article : Neuroscience Letters, 2008, 447 :82-86.

Lay summary
Mecp2 deficiency has been previously associated to a dysfunction of neurones synthetizing several neurotransmitters called catecholamines (dopamine, norepinephrine, epinephrine) in the mouse brainstem. This article demonstrates a deficit in catecholamines in the peripheral nervous system of the MECP2 deficient mice, in addition to the deficits that were already known in the central nervous system. Tyrosine hydroxylase (TH) is a protein that is necessary to synthetize catecholamines. The amount of tyrosine hydroxylase was thus measured in key organs of the autonomic nervous system of the MECP2 deficient mouse. The results show that the amounts of tyrosine hydroxylase are globally decreased in the peripheral nervous system of the MECP2 deficient mice. This article also reports that the respiratory response when oxygen levels are low is significantly increased in the MECP2 deficient mice. This means that there are defects in the perception of modifications in the environement, such as a decrease in oxygen levels. These results offer new insights to better understand the mechanisms leading to autonomic dysfunction in Rett syndrome.

30/11/2008

The first missense mutation causing Rett syndrome specifically affecting the MeCP2_e1 isoform

Publication date : novembre 2008
EuroRETT partner : Thierry Bienvenu, Paris
Authors : Fichou Y, Nectoux J, Bahi-Buisson N, Rosas-Vargas H, Girard B, Chelly J, Bienvenu T.
Link to the article : Neurogenetics, 2009, 10:127-133.

Lay summary
The MECP2 gene is coding for two proteins : MECP2_e1 that is strongly expressed in the brain and MECP2_e2 that is expressed at similar levels in all tissues. This article reports the identification of the first de novo mutation affecting a highly conserved amino-acid at the very beginning of the brain-dominant protein isoform MECP2_e1 in a girl with classical Rett syndrome. The missense mutation, p.Ala2Val, leads to severe developmental delay, microcephaly, no language, severe epilepsy, and cognitive impairment. These data provide further evidence for the major impact of a specific MECP2_e1 deficiency in the development of intellectual processing.

01/12/2008

Analysis of gene expression in the brain of the « Rett mouse »

Publication date : november 2008
EuroRETT partner : Manel Esteller, Madrid.
Authors  : Urdinguio RG, Lopez-Serra L, Lopez-Nieva P, Alaminos M, Diaz-Uriarte R, Fernandez AF, Esteller M.
Link to the article : PloS One, 2008, 3 :e3669.

Lay summary
This study aimed to identify new target genes regulated by Mecp2 in a mouse model of Rett syndrome. The authors have compared gene expression in three regions of the brain (cortex, midbrain, and cerebellum). Seven direct target genes of Mecp2 were identified : Fkbp5, Mobp, Plagl1, Ddc, Mllt2h, Eya2, and S100a9. Three additional genes were overexpressed due to an indirect effect of a lack of Mecp2 : Irak1, Prodh and Dlk1. These gene are excellent candidate genes for involvement in various features of Rett syndrome.

30/11/2008

Expression of MECP2 in the mouse brainstem

Publication date : october 2008
EuroRETT partner : Laurent Villard, Marseille.
Authors : Dura E, Villard L, Roux JC.
Link to the article : Brain Research, 2008, 1236 :176-184.

Lay summary
MECP2 is able to modulate the expression of target genes (to increase or to decrease their expression levels). All patients having a mutation in MECP2 are mentally retarded and most of them exhibit dysfunctions of the autonomic nervous system. Several of the affected functions are controlled by the brainstem. However, previous studies have not investigated the expression of MECP2 in the brainstem. In the present study, MEPC2 expression levels were quantified in different areas of the mouse brainstem between birth and 2 months of age (age when the mice die when they do not express MECP2). The results show that the expression of MECP2 is heterogeneous throughout the mouse brainstem after birth. MECP2 expression in each area studied is restricted to neurones and not to other cell types of the nervous system. The developmental pattern is characterized by an increase of the amount of MECP2 protein after birth. However, there is no obvious correlation between the developmental expression of MECP2 in a given area of the brainstem and the autonomic dysfunctions present in the patients having a mutation in MECP2. It is not the region expressing the largest amount of MECP2 protein that are the most severely affected in the brainstem.

30/11/2008

Cdkl5 expression is modulated during neuronal development

Publication date : october 2008
EuroRETT partners  : Nicoletta Landsberger, Charlotte Kilstrup-Nielsen, Busto Arsizio ; Vania Broccoli, Milan.
Authors : Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, Landsberger N.
Link to the article  : Journal of Biological Chemistry, 2008, 283 :30101-30111.

Lay summary
The CDKL5 gene is located on the X chromosome, like MECP2. Mutations in the CDKL5 gene have been identified in patients with Rett syndrome or neonatal epilepsie (West syndrome). These diseases share the common features of mental retardation and early seizures. To understand the role of the CDKL5 protein for nervous system functions, its expression in the mouse brain was studied and compared to that of MECP2. The two proteins share a general expression profile in the adult mouse brain. However, the amount of CDKL5 appears to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages. In the adult brain, CDKL5 is present in mature neurons but not in other cell types of the nervous system. This work also shows that the CDKL5 protein is able to shuttle between different cellular compartments (from or to the nucleus of the cell). Some mutant forms of the CDKL5 do not shuttle and stay in the nucleus. This impossibility to exit the nucleus could be at the origin of diseases associated with CDKL5 mutations.

30/11/2008

Review on mouse models of Rett syndrome

Publication date : septembre 2008
EuroRETT partner : Giovanni Laviola, Rome
Authors : Ricceri L, De Filippis B, Laviola G.
Link to the article : Behavioral Pharmacology, 2008, 19 :501-517.

Lay summary
The generation of mouse models for Rett syndrome provided a major breakthrough for Rett syndrome research. This review provides an overview of the behavioural domains so far investigated in these models, pharmacological and nonpharmacological interventions, as well as the genetic manipulations aimed at rescuing the disease.

30/11/2008

A chromosome 14 deletion causes Rett-like features

Publication date : august 2008
EuroRETT partner : Alessandra Renieri, Siena
Authors : Papa FT, Mencarelli MA, Caselli R, Katzaki E, Sampieri K, Meloni I, Ariani F, Longo I, Maggio A, Balestri P, Grosso S, Farnetani MA, Berardi R, Mari F, Renieri A.
Link to the article : American Journal of Medical Genetics part A, 2008, 146A :1994-1998.

Lay summary
This report describes a 7-year-old girl with a deletion of a large fragment of chromosome 14. The region is gene poor. Two genes in this region, called FOXG1B and PRKD1, are also deleted in a previously reported case with a very similar clinical picture. Both patients present the same dysmorphic features and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B is a gene that is known to promote the proliferation of young, immature neurones. A disruption of this gene was previsouly reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.

30/11/2008

Identification of FOXG1, responsible for the congenital variant of Rett Syndrome

Publication date : july 2008
EuroRETT partners : Alessandra Renieri, Siena ; Vania Broccoli, Milano.
Authors : Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A, Pollazzon M, Buoni S, Spiga O, Ricciardi S, Meloni I, Longo I, Mari F, Broccoli V, Zappella M, Renieri A.
Link to the article : American Journal of Human Genetics, 2008, 83 :89-93.

Lay summary
This article reports the identification of mutations in the FOXG1 gene in two patients affected by the congenital variant of Rett syndrome (disease present from birth). FOXG1 encodes a brain-specific transcriptional repressor that is essential for the early development of a region of the brain. Molecular analysis reveals that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in the postnatal cerebral cortex.

30/11/2008