Publications by authors named "Francois Bolduc"

37 Publications

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Insights Into Potato Spindle Tuber Viroid Quasi-Species From Infection to Disease.

Front Microbiol 2020 3;11:1235. Epub 2020 Jul 3.

RNA Group/Groupe ARN, Département de Biochimie, Faculté de Médecine des Sciences de la Santé, Pavillon de Recherche Appliquée au Cancer, Université de Sherbrooke, Sherbrooke, QC, Canada.

Viroids are non-coding RNA plant pathogens that are characterized by their possession of a high mutation level. Although the sequence heterogeneity in viroid infected plants is well understood, shifts in viroid population dynamics due to mutations over the course of infection remain poorly understood. In this study, the ten most abundant sequence variants of potato spindle tuber viroid RG1 (PSTVd) expressed at different time intervals in PSTVd infected tomato plants were identified by high-throughput sequencing. The sequence variants, forming a quasi-species, were subjected to both the identification of the regions favoring mutations and the effect of the mutations on viroid secondary structure and viroid derived small RNAs (vd-sRNA). At week 1 of PSTVd infection, 25% of the sequence variants were similar to the "master" sequence (i.e., the sequence used for inoculation). The frequency of the master sequence within the population increased to 70% at week 2 after PSTVd infection, and then stabilized for the rest of the disease cycle (i.e., weeks 3 and 4). While some sequence variants were abundant at week 1 after PSTVd infection, they tended to decrease in frequency over time. For example, the variants with insertions at positions 253 or 254, positions that could affect the Loop E as well as the metastable hairpin I structure that has been shown important during replication and viroid infectivity, resulted in decreased frequency. Data obtained by analysis of the viroid derived small RNAs (vd-sRNA) was also analyzed. A few mutants had the potential of positively affecting the viroid's accumulation by inducing the RNA silencing of the host's defense related genes. Variants with mutations that could negatively affect viroid abundance were also identified because their derived vd-sRNA were no longer capable of targeting any host mRNA or of changing its target sequence from a host defense gene to some other non-important host gene. Together, these findings open avenues into understanding the biological role of sequence variants, this viroid's interaction with host components, stable and metastable structures generated by mutants during the course of infection, and the influence of sequence variants on stabilizing viroid population dynamics.
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http://dx.doi.org/10.3389/fmicb.2020.01235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349936PMC
July 2020

Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.

Am J Hum Genet 2020 08 23;107(2):364-373. Epub 2020 Jul 23.

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany. Electronic address:

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413886PMC
August 2020

The Small Nuclear Ribonucleoprotein Polypeptide A (SNRPA) binds to the G-quadruplex of the BAG-1 5'UTR.

Biochimie 2020 Sep 4;176:122-127. Epub 2020 Jul 4.

RNA Group/Groupe ARN, Département de biochimie et de génomique fonctionnelle, Pavillon de Recherche Appliquée au Cancer, Université de Sherbrooke, 3201, Jean-Mignault, Sherbrooke, Québec, J1E 4K8, Canada. Electronic address:

The protein "BCL-2-associated athanogene-1" (BAG-1), which exists in multiple isoforms, promotes cancer cell survival and is overexpressed in many different cancers. As a result, BAG-1-targeted therapy appears to be a promising strategy with which to treat cancer. It has previously been shown that the 5'UTR of the BAG-1 mRNA contains a guanine rich region that folds into a G-quadruplex structure which can modulate both its cap-dependent and its cap-independent translation. Accumulating data regarding G-quadruplex binding proteins suggest that these proteins can play a central role in gene expression. Consequently, the identification of the proteins that could potentially bind to the G-quadruplex of the BAG-1 mRNA was undertaken. Label-free RNA pulldown assays were performed using protein extracts from colorectal cancer cells and this leads to the detection of RNA G4 binding proteins by LC-MS/MS. The use of G-quadruplex containing RNA, as well as of a mutated version, ensured that the proteins identified were specific for the RNA G-quadruplex structure and not just general RNA binding proteins. Following confirmation of the interaction, the Small Nuclear Ribonucleoprotein Polypeptide A (SNRPA) was shown to bind directly to the BAG-1 mRNA through the G-quadruplex, and knock down experiments in colorectal cancer cells suggested that it can modulate the expression level of BAG-1.
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http://dx.doi.org/10.1016/j.biochi.2020.06.013DOI Listing
September 2020

Prenatal fruit juice exposure enhances memory consolidation in male post-weanling Sprague-Dawley rats.

PLoS One 2020 28;15(1):e0227938. Epub 2020 Jan 28.

Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada.

Objectives: Nutritional intake during gestation is known to impact health outcomes for progeny. Correlational evidence in humans suggests that increased fruit consumption of pregnant mothers enhances infant cognitive development. Moreover, wild-type Drosophila supplemented with a combination of orange and tomato juice showed robust enhancements in performance on an associative olfactory memory task. The current study aimed to experimentally test the effects of prenatal fruit juice exposure in a non-human, mammalian model of learning and memory.

Methods: Across three separate birth cohorts, pregnant rats were given access to diluted tomato and orange juice (N = 2 per cohort), with control rats (N = 2 per cohort) receiving only water, in addition to standard rodent chow, throughout the duration of gestation, ending at parturition. Following weaning, male offspring were tested for learning and memory in a spatial version of the circular water maze and an auditory-cued fear-conditioning task.

Results: All pregnant rats increased fluid and food intake over the gestational period. Fruit juice-fed pregnant rats had increased fluid intake compared to control pregnant rats. When testing progeny, there were no effects of prenatal fruit juice on spatial learning, while it appeared to impair learning in fear conditioning relative to controls. However, we measured significant enhancements in both spatial memory and conditioned fear memory in the prenatal fruit-juice group compared to controls. Measures of vigilance, in response to the conditioned cue, were increased in prenatal fruit rats compared to controls, suggesting less generalized, and more adaptive, anxiety behaviours.

Discussion: Our results corroborate the human and Drosophila findings of prenatal fruit effects on behaviour, specifically that prenatal fruit juice exposure may be beneficial for early-life memory consolidation in rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227938PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986755PMC
April 2020

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

Stress Odorant Sensory Response Dysfunction in Fragile X Syndrome Mutants.

Front Mol Neurosci 2018 8;11:242. Epub 2018 Aug 8.

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Sensory processing dysfunction (SPD) is present in most patients with intellectual disability (ID) and autism spectrum disorder (ASD). Silencing expression of the Fragile X mental retardation 1 () gene leads to Fragile X syndrome (FXS), the most common single gene cause of ID and ASD. have a highly conserved FMR1 ortholog, . mutants display cognitive and social defects reminiscent of symptoms seen in individuals with FXS. We utilized a robust behavioral assay for sensory processing of the stress odorant (dSO) to gain a better understanding of the molecular basis of SPD in FXS. Here, we show that mutant flies present significant defects in dSO response. We found that expression in mushroom bodies is required for dSO processing. We also show that cyclic adenosine monophosphate (cAMP) signaling via PKA is activated after exposure to dSO and that several drugs regulating both cAMP and cyclic guanosine monophosphate (cGMP) levels significantly improved defects in dSO processing in mutant flies.
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http://dx.doi.org/10.3389/fnmol.2018.00242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092503PMC
August 2018

G-Quadruplexes influence pri-microRNA processing.

RNA Biol 2018 02 11;15(2):198-206. Epub 2017 Dec 11.

a Département de Biochimie, Pavillon de Recherche Appliquée sur le Cancer , Université de , Sherbrooke, 3201 Jean-Mignault, Sherbrooke , Québec , Canada.

RNA G-Quadruplexes (G4) have been shown to possess many biological functions, including the regulation of microRNA (miRNA) biogenesis and function. However, their impact on pri-miRNA processing remains unknown. We identified G4 located near the Drosha cleavage site in three distinct pri-miRNAs: pri-mir200c, pri-mir451a, and pri-mir497. The folding of the potential G4 motifs was determined in solution. Subsequently, mutations disrupting G4 folding led to important changes in the mature miRNAs levels in cells. Moreover, using small antisense oligonucleotides binding to the pri-miRNA, it was possible to modulate, either positively or negatively, the mature miRNA levels. Together, these data demonstrate that G4 motifs could contribute to the regulation of pri-mRNA processing, a novel role for G4. Considering that bio-informatics screening indicates that between 9% and 50% of all pri-miRNAs contain a putative G4, these structures possess interesting potential as future therapeutic targets.
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http://dx.doi.org/10.1080/15476286.2017.1405211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798953PMC
February 2018

Quantitative phenotypic and network analysis of 1q44 microdeletion for microcephaly.

Am J Med Genet A 2017 Apr;173(4):972-977

Division of Pediatric Neurology, University of Alberta, Edmonton, Alberta, Canada.

As genome wide techniques become more common, an increasing proportion of patients with intellectual disability (ID) are found to have genetic defects allowing genotype-phenotype correlations. Previously, AKT3 deletion was suggested to be responsible for microcephaly in patients with 1q43-q44 deletion syndrome, but this does not correspond to all cases. We report a case of a de novo 1q44 deletion in an 8-year-old boy with microcephaly in whom AKT3 is not deleted. We used a systematic review of the literature, our patient, and network analysis to gain a better understanding of the genetic basis of microcephaly in 1q deletion patients. Our analysis showed that while AKT3 deletion is associated with more severe (≤3 SD) microcephaly in 1q43-q44 deletion patients, other genes may contribute to microcephaly in AKT3 intact patients with microcephaly and 1q43-44 deletion syndrome. We identified a potential role for HNRNPU, SMYD3, NLRP3, and KIF26B in microcephaly. Overall, our study highlights the need for network analysis and quantitative measures reporting in the phenotypic analysis of a complex genetic syndrome related to copy number variation.
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http://dx.doi.org/10.1002/ajmg.a.38139DOI Listing
April 2017

Irregular G-quadruplexes Found in the Untranslated Regions of Human mRNAs Influence Translation.

J Biol Chem 2016 Oct 24;291(41):21751-21760. Epub 2016 Aug 24.

From the RNA Group/Groupe ARN, Département de Biochimie, Faculté de Médecine et Sciences de la Santé, Pavillon de Recherche Appliquée au Cancer, Université de Sherbrooke, Sherbrooke, Quebec J1E 4K8, Canada

G-quadruplex structures are composed of coplanar guanines and are found in both DNA and RNA. They are formed by the stacking of two or more G-quartets that are linked together by three loops. The current belief is that RNA G-quadruplexes include loops of l to 7 nucleotides in length, although recent evidence indicates that the central loop (loop 2) can be longer if loops 1 and 3 are limited to a single nucleotide each. With the objective of broadening the definition of irregular RNA G-quadruplexes, a bioinformatic search was performed to find potential G-quadruplexes located in the untranslated regions of human mRNAs (i.e. in the 5' and 3'-UTRs) that contain either a long loop 1 or 3 of up to 40 nucleotides in length. RNA molecules including the potential sequences were then synthesized and examined in vitro by in-line probing for the formation of G-quadruplex structures. The sequences that adopted a G-quadruplex structure were cloned into a luciferase dual vector and examined for their ability to modulate translation in cellulo Some irregular G-quadruplexes were observed to either promote or repress translation regardless of the position or the size of the long loop they possessed. Even if the composition of a RNA G-quadruplex is not quite completely understood, the results presented in this report clearly demonstrate that what defines a RNA G-quadruplex is much broader than what we previously believed.
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http://dx.doi.org/10.1074/jbc.M116.744839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076843PMC
October 2016

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Front Behav Neurosci 2016 30;10:136. Epub 2016 Jun 30.

McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva UniversityBronx, NY, USA; Jongens Laboratory, Department of Genetics, University of Pennsylvania School of MedicinePhiladelphia, PA, USA; Siegel Laboratory, Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania School of MedicinePhiladelphia, PA, USA.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.
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http://dx.doi.org/10.3389/fnbeh.2016.00136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928101PMC
July 2016

Cognitive Enhancement in Infants Associated with Increased Maternal Fruit Intake During Pregnancy: Results from a Birth Cohort Study with Validation in an Animal Model.

EBioMedicine 2016 Jun 22;8:331-340. Epub 2016 Apr 22.

Canadian Healthy Infant Longitudinal Development Study, Canada.

In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37; p<0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7; SE 1.8; p<0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca(2+)-Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila. Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.
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http://dx.doi.org/10.1016/j.ebiom.2016.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919537PMC
June 2016

Recurrent Diplopia in a Pediatric Patient with Bickerstaff Brainstem Encephalitis.

Case Rep Neurol Med 2016 17;2016:5240274. Epub 2016 May 17.

Department of Pediatrics, Edmonton Clinic Health Academy, University of Alberta, 11405 87 Avenue, Edmonton, AB, Canada T6G 1C9.

Introduction. Acute complete external ophthalmoplegia is a rare finding in clinical practice that is associated with diseases affecting the neuromuscular junction, the oculomotor nerves, or the brainstem. Ophthalmoplegia has been reported with acute ataxia in Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE). Up to 95% of these cases are associated with anti-GQ1b antibodies. Only a small number of cases of anti-GQ1b negative MFS have been documented in pediatric patients. This is the first case reporting a recurrence of ocular symptoms in an anti-GQ1b antibody negative patient with BBE. Case Presentation. An 8-year-old Caucasian boy presented with complete external ophthalmoplegia without ptosis, cerebellar ataxia, and a disturbance of consciousness. He had recently recovered from a confirmed Campylobacter jejuni infection. On subsequent laboratory testing he was anti-GQ1b antibody negative. He had a recurrence of diplopia at four-week follow-up. Conclusions. This patient's recurrence of diplopia was treated with a five-week course of oral corticosteroids which did not worsen his condition, and this may be a therapeutic option for similar patients. We will discuss the symptoms and treatment of reported pediatric cases of anti-GQ1b antibody negative cases of MFS and the variation between cases representing a spectrum of illness.
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http://dx.doi.org/10.1155/2016/5240274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886058PMC
June 2016

Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.

Am J Hum Genet 2016 May;98(5):1038-1046

Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863665PMC
May 2016

Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome.

Neurol Genet 2016 Apr 22;2(2):e58. Epub 2016 Mar 22.

Department of Pediatrics (X.H., R.S., A.M.D., F.V.B.), Neuroscience and Mental Health Institute (F.V.B.), and Department of Medical Genetics (O.C., F.V.B.), University of Alberta, Edmonton, Alberta, Canada.

Kleefstra syndrome (KS; OMIM #610253), formerly known as the 9q subtelomeric deletion syndrome, is an autosomal dominant cause of intellectual disability (ID) characterized by hypotonia and facial dysmorphisms.(1,2) The cause of KS is attributed to haploinsufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene (OMIM *607001) located at chromosome 9q34.3 (i.e., distal long arm of chromosome 9), either by microdeletion or point mutation. EHMT1 encodes a histone H3 methyltransferase at position Lys-9 (H3K9).(1-3).
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http://dx.doi.org/10.1212/NXG.0000000000000058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830196PMC
April 2016

Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms.

Hum Mol Genet 2016 Mar 6;25(6):1088-99. Epub 2016 Jan 6.

Institute for Neuroscience and Mental Health and Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada and

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP.
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http://dx.doi.org/10.1093/hmg/ddv632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764191PMC
March 2016

Genomic characterization of chromosome 8 pericentric trisomy.

Clin Case Rep 2015 Jul 20;3(7):570-7. Epub 2015 May 20.

Division of Pediatric Neuroscience, Stollery Children Hospital, University of Alberta Edmonton, Alberta, Canada ; Neuroscience and Mental Health Institute, University of Alberta Edmonton, Alberta, Canada.

We present a patient with trisomy 8p11.21q11.21 associated with language, gross motor, fine motor, and cognitive delay. Furthermore, using array-based comparative genomic hybridization, we identify the specific genes duplicated in our patient.
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http://dx.doi.org/10.1002/ccr3.234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527799PMC
July 2015

Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders.

J Vis Exp 2015 Jun 13(100):e52741. Epub 2015 Jun 13.

Department of Pediatrics, University of Alberta;

Locomotive defects resulting from neurodegenerative disorders can be a late onset symptom of disease, following years of subclinical degeneration, and thus current therapeutic treatment strategies are not curative. Through the use of whole exome sequencing, an increasing number of genes have been identified to play a role in human locomotion. Despite identifying these genes, it is not known how these genes are crucial to normal locomotive functioning. Therefore, a reliable assay, which utilizes model organisms to elucidate the role of these genes in order to identify novel targets of therapeutic interest, is needed more than ever. We have designed a sensitized version of the negative geotaxis assay that allows for the detection of milder defects earlier and has the ability to evaluate these defects over time. The assay is performed in a glass graduated cylinder, which is sealed with a wax barrier film. By increasing the threshold distance to be climbed to 17.5 cm and increasing the experiment duration to 2 min we have observed a greater sensitivity in detecting mild mobility dysfunctions. The assay is cost effective and does not require extensive training to obtain highly reproducible results. This makes it an excellent technique for screening candidate drugs in Drosophila mutants with locomotion defects.
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http://dx.doi.org/10.3791/52741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544889PMC
June 2015

From Learning to Memory: What Flies Can Tell Us about Intellectual Disability Treatment.

Front Psychiatry 2015 3;6:85. Epub 2015 Jun 3.

Department of Pediatrics, University of Alberta , Edmonton, AB , Canada ; Neuroscience and Mental Health Institute, University of Alberta , Edmonton, AB , Canada.

Intellectual disability (ID), previously known as mental retardation, affects 3% of the population and remains without pharmacological treatment. ID is characterized by impaired general mental abilities associated with defects in adaptive function in which onset occurs before 18 years of age. Genetic factors are increasing and being recognized as the causes of severe ID due to increased use of genome-wide screening tools. Unfortunately drug discovery for treatment of ID has not followed the same pace as gene discovery, leaving clinicians, patients, and families without the ability to ameliorate symptoms. Despite this, several model organisms have proven valuable in developing and screening candidate drugs. One such model organism is the fruit fly Drosophila. First, we review the current understanding of memory in human and its model in Drosophila. Second, we describe key signaling pathways involved in ID and memory such as the cyclic adenosine 3',5'-monophosphate (cAMP)-cAMP response element binding protein (CREB) pathway, the regulation of protein synthesis, the role of receptors and anchoring proteins, the role of neuronal proliferation, and finally the role of neurotransmitters. Third, we characterize the types of memory defects found in patients with ID. Finally, we discuss how important insights gained from Drosophila learning and memory could be translated in clinical research to lead to better treatment development.
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http://dx.doi.org/10.3389/fpsyt.2015.00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453272PMC
June 2015

Insulin signaling is acutely required for long-term memory in Drosophila.

Front Neural Circuits 2015 10;9. Epub 2015 Mar 10.

Neuroscience and Mental Health Institute, University of Alberta Edmonton, AB, Canada ; Department of Pediatrics, University of Alberta Edmonton, AB, Canada.

Memory formation has been shown recently to be dependent on energy status in Drosophila. A well-established energy sensor is the insulin signaling (InS) pathway. Previous studies in various animal models including human have revealed the role of insulin levels in short-term memory but its role in long-term memory remains less clear. We therefore investigated genetically the spatial and temporal role of InS using the olfactory learning and long-term memory model in Drosophila. We found that InS is involved in both learning and memory. InS in the mushroom body is required for learning and long-term memory whereas long-term memory specifically is impaired after InS signaling disruption in the ellipsoid body, where it regulates the level of p70s6k, a downstream target of InS and a marker of protein synthesis. Finally, we show also that InS is acutely required for long-term memory formation in adult flies.
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http://dx.doi.org/10.3389/fncir.2015.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354381PMC
November 2015

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

J Neurosci 2015 Jan;35(1):396-408

Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.
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http://dx.doi.org/10.1523/JNEUROSCI.1356-12.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287155PMC
January 2015

Elucidation of the structures of all members of the Avsunviroidae family.

Mol Plant Pathol 2014 Oct;15(8):767-79

Viroids are small single-stranded RNA pathogens which cause significant damage to plants. As their nucleic acids do not encode for any proteins, they are dependant solely on their structure for their propagation. The elucidation of the secondary structures of viroids has been limited because of the exhaustive and time consuming nature of classic approaches. Here, the method of high-throughput selective 2'-hydroxyl acylation analysed by primer extension (hSHAPE) has been adapted to probe the viroid structure. The data obtained using this method were then used as input for computer-assisted structure prediction using RNA structure software in order to determine the secondary structures of the RNA strands of both (+) and (–) polarities of all Avsunviroidae members, one of the two families of viroids. The resolution of the structures of all of the members of the family provides a global view of the complexity of these RNAs. The structural differences between the two polarities, and any plausible tertiary interactions, were also analysed. Interestingly, the structures of the (+) and (–) strands were found to be different for each viroid species. The structures of the recently isolated grapevine hammerhead viroid-like RNA strands were also solved. This species shares several structural features with the Avsunviroidae family, although its infectious potential remains to be determined.To our knowledge, this article represents the first report of the structural elucidation of a complete family of viroids.
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http://dx.doi.org/10.1111/mpp.12130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638799PMC
October 2014

Deep-sequencing of the peach latent mosaic viroid reveals new aspects of population heterogeneity.

PLoS One 2014 30;9(1):e87297. Epub 2014 Jan 30.

Département de biochimie, Faculté de médecine et des sciences de la santé, Pavillon de Recherche Appliquée au Cancer, Université de Sherbrooke, Sherbrooke, Québec, Canada.

Viroids are small circular single-stranded infectious RNAs characterized by a relatively high mutation level. Knowledge of their sequence heterogeneity remains largely elusive and previous studies, using Sanger sequencing, were based on a limited number of sequences. In an attempt to address sequence heterogeneity from a population dynamics perspective, a GF305-indicator peach tree was infected with a single variant of the Avsunviroidae family member Peach latent mosaic viroid (PLMVd). Six months post-inoculation, full-length circular conformers of PLMVd were isolated and deep-sequenced. We devised an original approach to the bioinformatics refinement of our sequence libraries involving important phenotypic data, based on the systematic analysis of hammerhead self-cleavage activity. Two distinct libraries yielded a total of 3,939 different PLMVd variants. Sequence variants exhibiting up to ∼17% of mutations relative to the inoculated viroid were retrieved, clearly illustrating the high level of divergence dynamics within a unique population. While we initially assumed that most positions of the viroid sequence would mutate, we were surprised to discover that ∼50% of positions remained perfectly conserved, including several small stretches as well as a small motif reminiscent of a GNRA tetraloop which are the result of various selective pressures. Using a hierarchical clustering algorithm, the different variants harvested were subdivided into 7 clusters. We found that most sequences contained an average of 4.6 to 6.4 mutations compared to the variant used to initially inoculate the plant. Interestingly, it was possible to reconstitute and compare the sequence evolution of each of these clusters. In doing so, we identified several key mutations. This study provides a reliable pipeline for the treatment of viroid deep-sequencing. It also sheds new light on the extent of sequence variation that a viroid population can sustain, and which may give rise to a quasispecies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087297PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907566PMC
September 2014

The use of a combination of computer-assisted structure prediction and SHAPE probing to elucidate the secondary structures of five viroids.

Mol Plant Pathol 2012 Sep 16;13(7):666-76. Epub 2012 Jan 16.

College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.

The elucidation of the structures of viroids, noncoding infectious RNA species, is paramount to obtain an understanding of the various aspects of their life cycles (including replication, transport and pathogenesis). In general, the secondary structures of viroids have been predicted using computer software programs which have been shown to possess several important limitations. Clearly, the predicted structure of a viroid needs to receive physical support prior to its use in the accurate interpretation of any mechanistic studies. Here, SHAPE probing coupled to computer-assisted structure prediction using the RNAstructure software program was employed to determine the structures of five viroids. These species belong to four genera of the Pospiviroidae family, and none have had their structure characterized in solution. In addition, several interesting questions were addressed by either studying various sequence variants or varying the SHAPE conditions. More importantly, this approach is novel in the study of viroids, and should be of significant aid in the determination of the structures of other RNA species.
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http://dx.doi.org/10.1111/j.1364-3703.2011.00776.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638829PMC
September 2012

Rearrangement of chromosome 14q with associated white matter disease.

Pediatr Neurol 2011 Aug;45(2):117-20

Division of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

We report the case of a 29-month-old boy with spasticity and periventricular white matter changes on magnetic resonance imaging in whom a complex rearrangement consisting of a de novo duplication of 14q32.31q32.33 and deletion of 14q32.33 was identified by array-based comparative genomic hybridization. Our case replicates some of the previous features associated with chromosome 14q duplication and deletion while expanding its clinical spectrum with pyramidal tract dysfunction signs and neuroimaging features. Genomic lesions should be considered in cases of leukodystrophies, and genome-wide studies such as array-based comparative genomic hybridization could be considered in the assessment of undefined white matter disorders.
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http://dx.doi.org/10.1016/j.pediatrneurol.2011.03.008DOI Listing
August 2011

Mapping studies of the Peach latent mosaic viroid reveal novel structural features.

Mol Plant Pathol 2011 Sep 17;12(7):688-701. Epub 2011 Feb 17.

RNA Group/Groupe ARN, Département de Biochimie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada, J1H 5N4.

Knowledge of the structure of a viroid is critically important to elucidate the roles played by the various RNA motifs in the steps of the viroid's life cycle. A new technique, RNA-selective 2'-hydroxyl acylation analysed by primer extension (SHAPE), has recently been shown to be fast, reliable and applicable to the study of various RNA molecules. Consequently, this method was used to probe sequence variants of Peach latent mosaic viroid (PLMVd). Initially, probing data from RNA strands of both polarities of the Siberian C variant confirmed the secondary structures previously determined using both conventional and fastidious approaches. Subsequently, analysis of an Alberta variant showed an identical structure for the strand of (-) polarity, but the (+) polarity strand exhibited two differences from the Siberian C variant: the P11-L11 stem-loop domain formed a cruciform structure, and nucleotides from loops L1 and L11 were involved in the formation of a pseudoknot. The existence of both of these motifs was confirmed by site-directed mutagenesis. The subsequent probing of 12 natural sequence variants led to the elucidation of the criteria governing the formation of this novel pseudoknot. Importantly, this study revealed that the heterogeneity of a viroid is not limited to its nucleotide sequence, but may also occur at the structural level.
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http://dx.doi.org/10.1111/j.1364-3703.2010.00703.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256235PMC
September 2011

Developmental disability: duplication of zinc finger transcription factors 673 and 674.

Pediatr Neurol 2010 Sep;43(3):209-12

Division of Pediatric Neurology, University of Alberta, Edmonton, Alberta, Canada.

The past decade has witnessed a tremendous increase in our ability to identify precise genetic etiologies of developmental delay and intellectual disability. Mutations in various transcription factors were found in patients with intellectual disability. Specifically, the importance of a subgroup of transcription factors containing zinc finger motifs have been increasingly recognized in developmental delay and intellectual disability. We present a patient with intellectual disability in whom the duplication of two genes, ZNF673 and ZNF674, was identified through array-based comparative genomic hybridization. Our report reinforces the role of zinc finger transcription factors in cognitive development. Furthermore, it illustrates that not only deletions, but duplications, can cause developmental delay and intellectual disability.
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http://dx.doi.org/10.1016/j.pediatrneurol.2010.04.016DOI Listing
September 2010

An assay for social interaction in Drosophila fragile X mutants.

Fly (Austin) 2010 Jul-Sep;4(3):216-25. Epub 2010 Jul 1.

Watson School of Biological Sciences, Cold Spring Harbor, NY, USA.

We developed a novel assay to examine social interactions in Drosophila and, as a first attempt, apply it here at examining the behavior of Drosophila Fragile X Mental Retardation gene (dfmr1) mutants. Fragile X syndrome is the most common cause of single gene intellectual disability (ID) and is frequently associated with autism. Our results suggest that dfmr1 mutants are less active than wild-type flies and interact with each other less often. In addition, mutants for one allele of dfmr1, dfmr1(B55), are more likely to come in close contact with a wild-type fly than another dfmr1(B55) mutant. Our results raise the possibility of defective social expression with preserved receptive abilities. We further suggest that the assay may be applied in a general strategy of examining endophenoypes of complex human neurological disorders in Drosophila, and specifically in order to understand the genetic basis of social interaction defects linked with ID.
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http://dx.doi.org/10.4161/fly.4.3.12280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322501PMC
February 2014

Fragile x mental retardation 1 and filamin a interact genetically in Drosophila long-term memory.

Front Neural Circuits 2010 8;3:22. Epub 2010 Jan 8.

Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor New York, NY, USA.

The last decade has witnessed the identification of single-gene defects associated with an impressive number of mental retardation syndromes. Fragile X syndrome, the most common cause of mental retardation for instance, results from disruption of the FMR1 gene. Similarly, Periventricular Nodular Heterotopia, which includes cerebral malformation, epilepsy and cognitive disabilities, derives from disruption of the Filamin A gene. While it remains unclear whether defects in common molecular pathways may underlie the cognitive dysfunction of these various syndromes, defects in cytoskeletal structure nonetheless appear to be common to several mental retardation syndromes. FMR1 is known to interact with Rac, profilin, PAK and Ras, which are associated with dendritic spine defects. In Drosophila, disruptions of the dFmr1 gene impair long-term memory (LTM), and the Filamin A homolog (cheerio) was identified in a behavioral screen for LTM mutants. Thus, we investigated the possible interaction between cheerio and dFmr1 during LTM formation in Drosophila. We show that LTM specifically is defective in dFmr1/cheerio double heterozygotes, while it is normal in single heterozygotes for either dFmr1 or cheerio. In dFmr1 mutants, Filamin (Cheerio) levels are lower than normal after spaced training. These observations support the notion that decreased actin cross-linking may underlie the persistence of long and thin dendritic spines in Fragile X patients and animal models. More generally, our results represent the first demonstration of a genetic interaction between mental retardation genes in an in vivo model system of memory formation.
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http://dx.doi.org/10.3389/neuro.04.022.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813723PMC
July 2011