Jacques L Michaud

Publications (32)271.96 Total impact

• Article: Mutations in SYNGAP1 Cause Intellectual Disability, Autism and a Specific form of Epilepsy by Inducing Haploinsufficiency.

  Martin H Berryer, Fadi F Hamdan, Laura L Klitten, Rikke S Møller, Lionel Carmant, Jeremy Schwartzentruber, Lysanne Patry, Sylvia Dobrzeniecka, Daniel Rochefort, Mathilde Neugnot, [......], Niels Tommerup, Ladonna Immken, Miriam H Beauchamp, Gayle Simpson Patel, Jacek Majewski, Mark A Tarnopolsky, Klaus Scheffzek, Helle Hjalgrim, Jacques L Michaud, Graziella Di Cristo
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  ABSTRACT: De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP-activating protein, cause non-syndromic intellectual disability (NSID). All disease-causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R]; c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5]; c.2212_2213del [p.S738X]; (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild-type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity-dependent pERK levels. In contrast, constructs expressing p.W362R, p.P562L or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.
  Human Mutation 11/2012; · 5.69 Impact Factor
• Source

  Available from: Sanjay Kumar Bharti

  Article: Identification and Biochemical Characterization of a Novel Mutation in DDX11 Causing Warsaw Breakage Syndrome.

  José-Mario Capo-Chichi, Sanjay Kumar Bharti, Joshua A Sommers, Tony Yammine, Eliane Chouery, Lysanne Patry, Guy A Rouleau, Mark E Samuels, Fadi F Hamdan, Jacques L Michaud, Robert M Brosh Jr, André Mégarbane, Zoha Kibar
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  ABSTRACT: Mutations in the gene encoding the iron-sulfur-containing DNA helicase DDX11 (ChlR1) were recently identified as a cause of a new recessive cohesinopathy, Warsaw breakage syndrome (WABS), in a single patient with severe microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Here, using homozygosity mapping in a Lebanese consanguineous family followed by exome sequencing, we identified a novel homozygous mutation (c.788G>A [p.R263Q]) in DDX11 in three affected siblings with severe intellectual disability and many of the congenital abnormalities reported in the WABS original case. Cultured lymphocytes from the patients showed increased mitomycin C-induced chromosomal breakage, as found in WABS. Biochemical studies of purified recombinant DDX11 indicated that the p.R263Q mutation impaired DDX11 helicase activity by perturbing its DNA binding and DNA-dependent ATP hydrolysis. Our findings thus confirm the involvement of DDX11 in WABS, describe its phenotypical spectrum, and provide novel insight into the structural requirement for DDX11 activity.
  Human Mutation 10/2012; · 5.69 Impact Factor
• Article: Mutations in TMEM231 cause Joubert syndrome in French Canadians.

  Myriam Srour, Fadi F Hamdan, Jeremy A Schwartzentruber, Lysanne Patry, Luis H Ospina, Michael I Shevell, Valérie Désilets, Sylvia Dobrzeniecka, Géraldine Mathonnet, Emmanuelle Lemyre, Christine Massicotte, Damian Labuda, Dina Amrom, Eva Andermann, Guillaume Sébire, Bruno Maranda, Forge Canada Consortium, Guy A Rouleau, Jacek Majewski, Jacques L Michaud
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  ABSTRACT: Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French-Canadian (FC) individuals. Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42, known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231(c.12T>A[p.Tyr4*]; c.625G>A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors. Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.
  Journal of Medical Genetics 09/2012; 49(10):636-41. · 6.36 Impact Factor
• Source

  Available from: PubMed Central

  Article: Homozygous deletion of Tenascin-R in a patient with intellectual disability.

  David Dufresne, Fadi F Hamdan, Jill A Rosenfeld, Beth Torchia, Bernard Rosenblatt, Jacques L Michaud, Myriam Srour
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  ABSTRACT: TNR encodes Tenascin-R, an extracellular matrix glycoprotein that is primarily expressed in the central nervous system. Loss of TNR impairs cognition, synaptic plasticity and motor abilities in mice, however its role in human neurodevelopment and cognition is less clear. The authors present the case of a child with intellectual disability and transient choreoathetosis. Array genomic hybridisation revealed a homozygous deletion involving only two genes, including TNR. Sequencing TNR in a cohort of 219 patients with intellectual disability did not identify any potential pathogenic mutations. This is the first report of a complete loss of TNR associated with intellectual disability. This study provides evidence of the important role of TNR in brain development and cognition in humans.
  Journal of Medical Genetics 06/2012; 49(7):451-4. · 6.36 Impact Factor
• Article: Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population.

  Myriam Srour, Jeremy Schwartzentruber, Fadi F Hamdan, Luis H Ospina, Lysanne Patry, Damian Labuda, Christine Massicotte, Sylvia Dobrzeniecka, José-Mario Capo-Chichi, Simon Papillon-Cavanagh, Mark E Samuels, Kym M Boycott, Michael I Shevell, Rachel Laframboise, Valérie Désilets, Bruno Maranda, Guy A Rouleau, Jacek Majewski, Jacques L Michaud
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  ABSTRACT: Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs*31], c.4804C>T [p.Arg1602*], and c.7477C>T [p.Arg2493*]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.
  The American Journal of Human Genetics 03/2012; 90(4):693-700. · 10.60 Impact Factor
• Article: Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy.

  Fadi F Hamdan, Hirotomo Saitsu, Kiyomi Nishiyama, Julie Gauthier, Sylvia Dobrzeniecka, Dan Spiegelman, Jean-Claude Lacaille, Jean-Claude Décarie, Naomichi Matsumoto, Guy A Rouleau, Jacques L Michaud
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  ABSTRACT: Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the α-II subunit of spectrin (SPTAN1) were recently identified in two patients with intellectual disability (ID), infantile spasms (IS), hypomyelination, and brain atrophy. These mutations affected the C-terminal domain of the protein, which contains the nucleation site of the α/β spectrin heterodimer. By screening SPTAN1 in 95 patients with idiopathic ID, we found a de novo in-frame mutation (p.Q2202del) in the same C-terminal domain in a patient with mild generalized epilepsy and pontocerebellar atrophy, but without IS, hypomyelination, or other brain structural defects, allowing us to define the core phenotype associated with these C-terminal SPTAN1 mutations. We also found a de novo missense variant (p.R566P) of unclear clinical significance in a patient with non-syndromic ID. These two mutations induced different patterns of aggregation between spectrin subunits in transfected neuronal cell lines, providing a paradigm for the classification of candidate variants.
  European journal of human genetics: EJHG 01/2012; 20(7):796-800. · 3.56 Impact Factor
• Article: Mutations in NOTCH2 in families with Hajdu-Cheney syndrome.

  Jacek Majewski, Jeremy A Schwartzentruber, Aurore Caqueret, Lysanne Patry, Janet Marcadier, Jean-Pierre Fryns, Kym M Boycott, Louis-Georges Ste-Marie, Fergus E McKiernan, Ivo Marik, Hilde Van Esch, Jacques L Michaud, Mark E Samuels
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  ABSTRACT: Hajdu-Cheney syndrome (HCS) is a rare genetic disorder whose hallmark is acro-osteolysis, shortening of terminal phalanges, and generalized osteoporosis. We assembled a cohort of seven families with the condition and performed whole exome resequencing on a selected set of affected patients. One protein-coding gene, NOTCH2, carried heterozygous truncating variants in all patients and their affected family members. Our results replicate recently published studies of HCS and further support this as the causal gene for the disorder. In total, we identified five novel and one previously reported mutation, all clustered near the carboxyl terminus of the gene, suggesting an allele specific genotype-phenotype effect since other mutations in NOTCH2 have been reported to cause a form of Alagille syndrome. Notch-mediated signaling is known to play a role in bone metabolism. Our results support a potential therapeutic role for Notch pathways in treatment of osteoporosis.
  Human Mutation 06/2011; 32(10):1114-7. · 5.69 Impact Factor
• Article: Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.

  Julie Gauthier, Tabrez J Siddiqui, Peng Huashan, Daisaku Yokomaku, Fadi F Hamdan, Nathalie Champagne, Mathieu Lapointe, Dan Spiegelman, Anne Noreau, Ronald G Lafrenière, [......], Ridha Joober, Marie-Odile Krebs, Lynn E DeLisi, Laurent Mottron, Eric Fombonne, Jacques L Michaud, Pierre Drapeau, Salvatore Carbonetto, Ann Marie Craig, Guy A Rouleau
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  ABSTRACT: Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.
  Human Genetics 03/2011; 130(4):563-73. · 5.07 Impact Factor
• Article: Intellectual disability without epilepsy associated with STXBP1 disruption.

  Fadi F Hamdan, Julie Gauthier, Sylvia Dobrzeniecka, Anne Lortie, Laurent Mottron, Michel Vanasse, Guy D'Anjou, Jean Claude Lacaille, Guy A Rouleau, Jacques L Michaud
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  ABSTRACT: STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of secretory vesicles to the presynaptic membrane for the release of neurotransmitters. De novo missense mutations in STXBP1 were recently reported in patients with Ohtahara syndrome, a form of encephalopathy with severe early-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in 95 patients with non-syndromic intellectual disability (NSID) revealed de novo truncating mutations in two patients who also showed severe non-specific epilepsy, suggesting that STXBP1 disruption has the potential of causing a wide spectrum of epileptic disorders in association with intellectual disability. Here, we report on the mutational screening of STXBP1 in a different series of 50 patients with NSID and the identification of a novel de novo truncating mutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no history of epilepsy. This is the first report of a patient with a truncating mutation in STXBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption.
  European journal of human genetics: EJHG 03/2011; 19(5):607-9. · 3.56 Impact Factor
• Article: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.

  Fadi F Hamdan, Julie Gauthier, Yoichi Araki, Da-Ting Lin, Yuhki Yoshizawa, Kyohei Higashi, A-Reum Park, Dan Spiegelman, Sylvia Dobrzeniecka, Amélie Piton, [......], Myriam Srour, Ronald G Lafrenière, Pierre Drapeau, Jean Claude Lacaille, Eunjoon Kim, Jae-Ran Lee, Kazuei Igarashi, Richard L Huganir, Guy A Rouleau, Jacques L Michaud
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  ABSTRACT: Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.
  The American Journal of Human Genetics 03/2011; 88(3):306-16. · 10.60 Impact Factor
• Article: Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome.

  Duane L Guernsey, Makoto Matsuoka, Haiyan Jiang, Susan Evans, Christine Macgillivray, Mathew Nightingale, Scott Perry, Meghan Ferguson, Marissa LeBlanc, Jean Paquette, [......], Andrew Orr, Chris R McMaster, Jacques L Michaud, Cheri Deal, Sylvie Langlois, Duane W Superneau, Sandhya Parkash, Mark Ludman, David L Skidmore, Mark E Samuels
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  ABSTRACT: Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism.
  Nature Genetics 02/2011; 43(4):360-4. · 35.53 Impact Factor
• Article: De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.

  Fadi F Hamdan, Hussein Daoud, Amélie Piton, Julie Gauthier, Sylvia Dobrzeniecka, Marie-Odile Krebs, Ridha Joober, Jean-Claude Lacaille, Amélie Nadeau, Jeff M Milunsky, Zhenyuan Wang, Lionel Carmant, Laurent Mottron, Miriam H Beauchamp, Guy A Rouleau, Jacques L Michaud
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  ABSTRACT: Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID. To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals. We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects. We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.
  Biological psychiatry 01/2011; 69(9):898-901. · 8.93 Impact Factor
• Article: De novo truncating mutation in Kinesin 17 associated with schizophrenia.

  Julien Tarabeux, Nathalie Champagne, Edna Brustein, Fadi F Hamdan, Julie Gauthier, Mathieu Lapointe, Claudia Maios, Amélie Piton, Dan Spiegelman, Edouard Henrion, [......], Ferid Fathalli, Eric Fombonne, Laurent Mottron, Nadine Forget-Dubois, Michel Boivin, Jacques L Michaud, Ronald G Lafrenière, Pierre Drapeau, Marie-Odile Krebs, Guy A Rouleau
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  ABSTRACT: Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ. As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish. Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect. Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder.
  Biological psychiatry 10/2010; 68(7):649-56. · 8.93 Impact Factor
• Article: De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.

  Fadi F Hamdan, Hussein Daoud, Daniel Rochefort, Amélie Piton, Julie Gauthier, Mathieu Langlois, Gila Foomani, Sylvia Dobrzeniecka, Marie-Odile Krebs, Ridha Joober, Ronald G Lafrenière, Jean-Claude Lacaille, Laurent Mottron, Pierre Drapeau, Miriam H Beauchamp, Michael S Phillips, Eric Fombonne, Guy A Rouleau, Jacques L Michaud
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  ABSTRACT: Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.
  The American Journal of Human Genetics 10/2010; 87(5):671-8. · 10.60 Impact Factor
• Source

  Available from: PubMed Central

  Article: Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.

  Volkan Seyrantepe, Pablo Lema, Aurore Caqueret, Larbi Dridi, Samar Bel Hadj, Stephane Carpentier, Francine Boucher, Thierry Levade, Lionel Carmant, Roy A Gravel, Edith Hamel, Pascal Vachon, Graziella Di Cristo, Jacques L Michaud, Carlos R Morales, Alexey V Pshezhetsky
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  ABSTRACT: Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2) to G(M3) ganglioside. Hexa(-/-) mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2) ganglioside via a lysosomal sialidase into glycolipid G(A2), which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4(-/-);Hexa(-/-)) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa(-/-) or Neu4(-/-) siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating G(M2) ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa(-/-) mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa(-/-) mice.
  PLoS Genetics 09/2010; 6(9). · 8.69 Impact Factor
• Article: Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4.

  Duane L Guernsey, Haiyan Jiang, Julie Hussin, Marc Arnold, Khalil Bouyakdan, Scott Perry, Tina Babineau-Sturk, Jill Beis, Nadine Dumas, Susan C Evans, [......], Lysanne Patry, Andrea L Rideout, Aidan Thomas, Andrew Orr, Ingrid Hoffmann, Jacques L Michaud, Philip Awadalla, David C Meek, Mark Ludman, Mark E Samuels
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  ABSTRACT: Primary microcephaly is a rare condition in which brain size is substantially diminished without other syndromic abnormalities. Seven autosomal loci have been genetically mapped, and the underlying causal genes have been identified for MCPH1, MCPH3, MCPH5, MCPH6, and MCPH7 but not for MCPH2 or MCPH4. The known genes play roles in mitosis and cell division. We ascertained three families from an Eastern Canadian subpopulation, each with one microcephalic child. Homozygosity analysis in two families using genome-wide dense SNP genotyping supported linkage to the published MCPH4 locus on chromosome 15q21.1. Sequencing of coding exons of candidate genes in the interval identified a nonconservative amino acid change in a highly conserved residue of the centrosomal protein CEP152. The affected children in these two families were both homozygous for this missense variant. The third affected child was compound heterozygous for the missense mutation plus a second, premature-termination mutation truncating a third of the protein and preventing its localization to centrosomes in transfected cells. CEP152 is the putative mammalian ortholog of Drosphila asterless, mutations in which affect mitosis in the fly. Published data from zebrafish are also consistent with a role of CEP152 in centrosome function. By RT-PCR, CEP152 is expressed in the embryonic mouse brain, similar to other MCPH genes. Like some other MCPH genes, CEP152 shows signatures of positive selection in the human lineage. CEP152 is a strong candidate for the causal gene underlying MCPH4 and may be an important gene in the evolution of human brain size.
  The American Journal of Human Genetics 07/2010; 87(1):40-51. · 10.60 Impact Factor
• Article: [De novo mutations in SYNGAP1 associated with non-syndromic mental retardation].

  Fadi F Hamdan, Julie Gauthier, Guy A Rouleau, Jacques L Michaud
  Medecine sciences: M/S 02/2010; 26(2):133-5. · 0.64 Impact Factor
• Article: Impact of Sim1 gene dosage on the development of the paraventricular and supraoptic nuclei of the hypothalamus.

  Sabine Michaëlle Duplan, Francine Boucher, Lubomir Alexandrov, Jacques L Michaud
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  ABSTRACT: The bHLH-PAS transcription SIM1 is required for the development of all neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. Mice with a loss of Sim1 die within a few days of birth, presumably because of the lack of a PVN and SON. In contrast, mice with a decrease of Sim1 survive, are hyperphagic and become obese. The mechanism by which Sim1 controls food intake remains unclear. Here we show that the development of specific PVN and SON cell types is sensitive to Sim1 gene dosage. Sim1 haploinsufficiency reduces the number of vasopressin (AVP)- and oxytocin-producing cells in the PVN by about 50 and 80%, respectively, but does not affect the development of Crh, Trh and Ss neurons. A decrease of AVP-producing cells increases the sensitivity of Sim1 heterozygous mice to chronic dehydration. Moreover, retrograde labelling showed a 70% reduction of PVN neurons projecting to the dorsal vagal complex, raising the possibility that a decrease of these axons contributes to the hyperphagia of Sim1(+/-) mice. Sim1 haploinsufficiency is thus associated with a decrease of several PVN/SON cell types, which has the potential of affecting distinct homeostatic processes.
  European Journal of Neuroscience 12/2009; 30(12):2239-49. · 3.63 Impact Factor
• Article: No association between SRGAP3/MEGAP haploinsufficiency and mental retardation.

  Fadi F Hamdan, Julie Gauthier, Stéphanie Pellerin, Sylvia Dobrzeniecka, Claude Marineau, Eric Fombonne, Laurent Mottron, Ronald G Lafrenière, Pierre Drapeau, Jean Claude Lacaille, Guy A Rouleau, Jacques L Michaud
  Archives of neurology 06/2009; 66(5):675-6. · 6.31 Impact Factor
• Article: De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.

  Fadi F Hamdan, Amélie Piton, Julie Gauthier, Anne Lortie, François Dubeau, Sylvia Dobrzeniecka, Dan Spiegelman, Anne Noreau, Stéphanie Pellerin, Mélanie Côté, Edouard Henrion, Eric Fombonne, Laurent Mottron, Claude Marineau, Pierre Drapeau, Ronald G Lafrenière, Jean Claude Lacaille, Guy A Rouleau, Jacques L Michaud
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  ABSTRACT: We sequenced genes coding for components of the SNARE complex (STX1A, VAMP2, SNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1), which are essential for neurotransmission, in 95 patients with idiopathic mental retardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.169+1G>A) in two patients with severe mental retardation and nonsyndromic epilepsy. Reverse transcriptase polymerase chain reaction and sequencing showed that the splicing mutation creates a stop codon downstream of exon-3. No de novo or deleterious mutations in STXBP1 were found in 190 control subjects, or in 142 autistic patients. These results suggest that STXBP1 disruption is associated with autosomal dominant mental retardation and nonsyndromic epilepsy.
  Annals of Neurology 04/2009; 65(6):748-53. · 11.09 Impact Factor