Mowat-Wilson syndrome: neurological and molecular study in seven patients

Paz, José Albino da; Kim, Chong; Goossens, M.; Giurgea, Irina; Marques-Dias, Maria Joaquina

doi:10.1590/0004-282x20140182

Cited by 15 publications

(10 citation statements)

References 19 publications

(35 reference statements)

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“…All other parameters were found to be in the normal range. In summary, spectral EEG analysis of ArhGAP15 −/− mice shows an increase in the relative power of medium and high frequencies (α, β and γ ranges), a significant increase in the θ low activity (4–6 Hz) and a mild shift of MDF towards lower frequency (α and θ ranges), similar to the mild slowing of background activity seen in most Mowat-Wilson syndrome patients 21 , 22 . These latter results are in accordance with the reduced complexity of the cortical network previously described.…”

Section: Resultssupporting

confidence: 54%

Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics

Zamboni

Armentano

Berto

et al. 2018

Sci Rep

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The small-GTPase Rac1 is a key molecular regulator linking extracellular signals to actin cytoskeleton dynamics. Loss-of-function mutations in RAC1 and other genes of the Rac signaling pathway have been implicated in the pathogenesis of Intellectual Disability (ID). The Rac1 activity is negatively controlled by GAP proteins, however the effect of Rac1 hyperactivity on neuronal networking in vivo has been poorly studied. ArhGAP15 is a Rac-specific negative regulator, expressed in the main subtypes of pyramidal cortical neurons. In the absence of ArhGAP15, cortical pyramidal neurons show defective neuritogenesis, delayed axonal elongation, reduced dendritic branching, both in vitro and in vivo. These phenotypes are associated with altered actin dynamics at the growth cone due to increased activity of the PAK-LIMK pathway and hyperphosphorylation of ADF/cofilin. These results can be explained by shootin1 hypo-phosphorylation and uncoupling with the adhesion system. Functionally, ArhGAP15−/− mice exhibit decreased synaptic density, altered electroencephalographic rhythms and cognitive deficits. These data suggest that both hypo- and hyperactivation of the Rac pathway due to mutations in Rac1 regulators can result in conditions of ID, and that a tight regulation of Rac1 activity is required to attain the full complexity of the cortical networks.

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Section: Resultssupporting

confidence: 54%

Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics

Zamboni

Armentano

Berto

et al. 2018

Sci Rep

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“…Based on the relationships between Btd and epilepsy described in the literature, the variant of this gene in the GASH/Sal could also be important for its phenotype, although Btd is not involved in any significantly enriched pathway. Similarly, several studies have shown that heterozygous mutations of the Zeb2 gene cause the Mowat-Wilson syndrome, which is characterized by seizures with onset in the second year of life, among other symptoms [58][59][60][61][62]. The gene Zeb2 encodes the zinc finger E-box binding homeobox 2 protein.…”

Section: Plos Onementioning

confidence: 99%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

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Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate-and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arh-gef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that PLOS ONE PLOS ONE | https://doi.

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“…The small sample size in the current study precluded examining healthrelated variables such as seizures, use of anti-epileptic medication, and agenesis of the corpus callosum. However, the potential for epilepsy to impact sleep in people MWS warrants further investigation, given the high rate of epilepsy and the previous findings that seizures in this group are more frequent during drowsiness and sleep [Cordelli et al, 2013;Paz et al, 2015]. Furthermore, not only might frequent epileptiform anomalies be disturbing sleep of people with MWS, but as Cordelli et al [2013] argue, there is the potential that this impacts cognitive performance.…”

Section: Discussionmentioning

confidence: 93%

“…Yet, over 30% showed clinically significant levels of behavioral or emotional disturbance-which was not significantly different from the age and ID-matched comparison group. Seizures affect approximately 80% of individuals with MWS [Garavelli and Cerruti-Mainardi, 2007], and may be more frequent during drowsiness and sleep [Cordelli et al, 2013;Paz et al, 2015]. Adlington et al [2006] describe a 10-yearold male with MWS with seizures who showed night-settling problems and early waking.…”

Section: Introductionmentioning

confidence: 99%

Sleep disturbance in Mowat–Wilson syndrome

Evans

Mowat

Wilson

et al. 2015

American J of Med Genetics Pt A

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Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome caused by a heterozygous mutation or deletion of the ZEB2 gene. It is characterized by a distinctive facial appearance in association with intellectual disability (ID) and variable other features including agenesis of the corpus callosum, seizures, congenital heart defects, microcephaly, short stature, hypotonia, and Hirschsprung disease. The current study investigated sleep disturbance in people with MWS. In a series of unstructured interviews focused on development and behaviors in MWS, family members frequently reported sleep disturbance, particularly early-morning waking and frequent night waking. The Sleep Disturbance Scale for Children (SDSC) was therefore administered to a sample of 35 individuals with MWS, along with the Developmental Behaviour Checklist (DBC) to measure behavioral and emotional disturbance. A high level of sleep disturbance was found in the MWS sample, with 53% scoring in the borderline range and 44% in the clinical disorder range for at least one subscale of the SDSC. Scores were highest for the Sleep-wake transition disorders subscale, with 91% of participants reaching at least the borderline disorder range. A significant positive association was found between total scores on the SDSC and the DBC Total Behaviour Problem Score. These results suggest that sleep disorders should be screened for in people with MWS, and where appropriate, referrals to sleep specialists made for management of sleep problems.

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Mowat-Wilson syndrome: neurological and molecular study in seven patients

Cited by 15 publications

References 19 publications

Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics

Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics

Analysis of gene variants in the GASH/Sal model of epilepsy

Sleep disturbance in Mowat–Wilson syndrome

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