François Rivier

Publications (39)137.6 Total impact

• Article: Validation of high-resolution DNA melting analysis for mutation scanning of the CDKL5 gene: Identification of novel mutations.

  Laure Raymond, Bertrand Diebold, Céline Leroux, Hélène Maurey, Valérie Drouin-Garraud, Andre Delahaye, Olivier Dulac, Julia Metreau, Gia Melikishvili, Annick Toutain, François Rivier, Nadia Bahi-Buisson, Thierry Bienvenu
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  ABSTRACT: Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been predominantly described in epileptic encephalopathies of female, including infantile spasms with Rett-like features. Up to now, detection of mutations in this gene was made by laborious, expensive and/or time consuming methods. Here, we decided to validate high-resolution melting analysis (HRMA) for mutation scanning of the CDKL5 gene. Firstly, using a large DNA bank consisting to 34 samples carrying different mutations and polymorphisms, we validated our analytical conditions to analyse the different exons and flanking intronic sequences of the CDKL5 gene by HRMA. Secondly, we screened CDKL5 by both HRMA and denaturing high performance liquid chromatography (dHPLC) in a cohort of 135 patients with early-onset seizures. Our results showed that point mutations and small insertions and deletions can be reliably detected by HRMA. Compared to dHPLC, HRMA profiles are more discriminated, thereby decreasing unnecessary sequencing. In this study, we identified eleven novel sequence variations including four pathogenic mutations (2.96% prevalence). HRMA appears cost-effective, easy to set up, highly sensitive, non-toxic and rapid for mutation screening, ideally suited for large genes with heterogeneous mutations located along the whole coding sequence, such as the CDKL5 gene.
  Gene 10/2012; · 2.34 Impact Factor
• Article: 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements.

  Lila Allou, Laetitia Lambert, Daniel Amsallem, Eric Bieth, Patrick Edery, Anne Destrée, François Rivier, David Amor, Elizabeth Thompson, Julian Nicholl, Michael Harbord, Christophe Nemos, Aline Saunier, Aissa Moustaïne, Adeline Vigouroux, Philippe Jonveaux, Christophe Philippe
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  ABSTRACT: The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (-4 to-6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.European Journal of Human Genetics advance online publication, 27 June 2012; doi:10.1038/ejhg.2012.127.
  European journal of human genetics: EJHG 06/2012; · 3.56 Impact Factor
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  Available from: Dominique Mornet

  Article: E2F transcription factor-1 deficiency reduces pathophysiology in the mouse model of Duchenne muscular dystrophy through increased muscle oxidative metabolism.

  Emilie Blanchet, Jean-Sébastien Annicotte, Ludivine A Pradelli, Gérald Hugon, Stéfan Matecki, Dominique Mornet, François Rivier, Lluis Fajas
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  ABSTRACT: E2F1 deletion leads to increased mitochondrial number and function, increased body temperature in response to cold and increased resistance to fatigue with exercise. Since E2f1-/- mice show increased muscle performance, we examined the effect of E2f1 genetic inactivation in the mdx background, a mouse model of Duchenne muscular dystrophy (DMD). E2f1-/-;mdx mice demonstrated a strong reduction of physiopathological signs of DMD, including preservation of muscle structure, decreased inflammatory profile, increased utrophin expression, resulting in better endurance and muscle contractile parameters, comparable to normal mdx mice. E2f1 deficiency in the mdx genetic background increased the oxidative metabolic gene program, mitochondrial activity and improved muscle functions. Interestingly, we observed increased E2F1 protein levels in DMD patients, suggesting that E2F1 might represent a promising target for the treatment of DMD.
  Human Molecular Genetics 06/2012; 21(17):3910-7. · 7.64 Impact Factor
• Article: Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene.

  Aliya Ishmukhametova, Philippe Khau Van Kien, Déborah Méchin, Delphine Thorel, Marie-Claire Vincent, François Rivier, Christine Coubes, Véronique Humbertclaude, Mireille Claustres, Sylvie Tuffery-Giraud
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  ABSTRACT: We report on the effectiveness of a custom-designed oligonucleotide-based comparative genomic hybridization microarray (array-CGH) to interrogate copy number across the entire 2.2-Mb genomic region of the DMD gene and its applicability in diagnosis. The high-resolution array-CGH, we developed, successfully detected a series of 42 previously characterized large rearrangements of various size, localization and type (simple or complex deletions, duplications, triplications) and known intronic CNVs/Indels. Moreover, the technique succeeded in identifying a small duplication of only 191 bp in one patient previously negative for DMD mutation. Accurate intronic breakpoints localization by the technique enabled subsequent junction fragments identification by sequencing in 86% of cases (all deletion cases and 62.5% of duplication cases). Sequence examination of the junctions supports a role of microhomology-mediated processes in the occurrence of DMD large rearrangements. In addition, the precise knowledge of the sequence context at the breakpoints and analysis of the resulting consequences on maturation of pre-mRNA contribute to elucidating the cause of discrepancies in phenotype/genotype correlations in some patients. Thereby, the array-CGH proved to be a highly efficient and reliable diagnostic tool, and the new data it provides will have many potential implications in both, clinics and research.
  European journal of human genetics: EJHG 04/2012; 20(10):1096-100. · 3.56 Impact Factor
• Article: Motor and respiratory heterogeneity in Duchenne patients: implication for clinical trials.

  Véronique Humbertclaude, Dalil Hamroun, Kamel Bezzou, Carole Bérard, Odile Boespflug-Tanguy, Christine Bommelaer, Emmanuelle Campana-Salort, Claude Cances, Brigitte Chabrol, Marie-Christine Commare, [......], Elisabeth Ollagnon-Roman, Christian Richelme, François Rivier, Sabrina Sacconi, Vincent Tiffreau, Carole Vuillerot, Marie-Christine Picot, Mireille Claustres, Christophe Béroud, Sylvie Tuffery-Giraud
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  ABSTRACT: Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD). The French dystrophinopathy database provided clinical, histochemical and molecular data of 278 DMD patients (mean longitudinal follow-up: 14.2 years). Diagnosis was based on mutation identification in the DMD gene. Three groups were defined according to the age at ambulation loss: before 8 years (group A); between 8 and 11 years (group B); between 11 and 16 years (group C). Motor and respiratory declines were statistically different between the three groups, as opposed to heart involvement. When acquired, running ability was lost at the mean age of 5.41 (group A), 7.11 (group B), 9.19 (group C) years; climbing stairs ability at 6.24 (group A), 7.99 (group B), 10,42 (group C) years, and ambulation at 7.10 (group A), 9.25 (group B), 12.01 (group C) years. Pulmonary growth stopped at 10.26 (group A), 12.45 (group B), 14.58 (group C) years. Then, forced vital capacity decreased at the rate of 8.83 (group A), 7.52 (group B), 6.03 (group C) percent per year. Phenotypic variability did not rely on specific mutational spectrum. Beside the most common form of DMD (group B), we provide detailed description on two extreme clinical subgroups: a severe one (group A) characterized by early severe motor and respiratory decline and a milder subgroup (group C). Compared to group B or C, four to six times fewer patients from group A are needed to detect the same decrease in disease progression in a clinical trial.
  European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 09/2011; 16(2):149-60. · 2.01 Impact Factor
• Article: Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.

  Romain Micol, Lilia Ben Slama, Felipe Suarez, Loïc Le Mignot, Julien Beauté, Nizar Mahlaoui, Catherine Dubois d'Enghien, Anthony Laugé, Janet Hall, Jérôme Couturier, [......], Olivier Hermine, Capucine Picard, Despina Moshous, Bénédicte Neven, Fanny Lanternier, Stéphane Blanche, Marc Tardieu, Marianne Debré, Alain Fischer, Dominique Stoppa-Lyonnet
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  ABSTRACT: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.
  The Journal of allergy and clinical immunology 06/2011; 128(2):382-9.e1. · 9.17 Impact Factor
• Article: Benign paroxysmal vertigo of childhood: long-term outcome.

  Benjamin Krams, Bernard Echenne, Julie Leydet, François Rivier, Agathe Roubertie
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  ABSTRACT: Benign paroxysmal vertigo (BPV) is characterized by recurrent attacks of dizziness in a healthy child. Complete recovery typically takes place during childhood, and an epidemiological link with migraine has been pointed out. Nevertheless, data concerning long-term patient outcome are scarce. We analyzed the clinical data of 17 patients diagnosed with BPV between 1991 and 2008 in our neuropediatric department; we particularly focused on family medical history and long-term patient outcome by reviewing their medical files and by interviewing the families with a standardized questionnaire administered by phone. Thirteen families responded to the questionnaire, performed 1.1 to 24.5 years after onset. Among 10 patients older than 11 years of age, five continue to suffer attacks of vertigo. Median age at recovery was six years. Nine subjects exhibited migraine, including all six aged 15 years or older. There was a first-degree history of migraine in eight out of 13 children. BPV may not be a homogeneous condition, as some children have a poorer prognosis than others. The strong link with migraine, already noticed by previous authors, led us to discuss the pathophysiology of this condition.
  Cephalalgia 03/2011; 31(4):439-43. · 3.43 Impact Factor
• Source

  Available from: Nadia Bahi-Buisson

  Article: A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization.

  Tangui Le Guen, Yann Fichou, Juliette Nectoux, Nadia Bahi-Buisson, François Rivier, Nathalie Boddaert, Bertrand Diebold, Delphine Héron, Jamel Chelly, Thierry Bienvenu
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  ABSTRACT: The forkhead box G1 (FOXG1)gene has recently been associated with the congenital variant of Rett syndrome, and so far 17 mutations have been reported. We screened the coding region in 150 patients affected by postnatal microcephaly, and identified two mutations: the c.326C>T (p.P109L) substitution inherited from the healthy father; and the de novo c.730C>T transition, which induces the p.R244C mutation within the DNA-binding forkhead domain. This latter mutation is carried by an 8-year-old girl, who presented a phenotype reminiscent of the congenital variant of Rett syndrome. Immunofluorescence analysis of the wild-type protein revealed a homogeneous nuclear staining excluding the nucleoli, while the p.R244C mutant showed abnormal nuclear foci in a large proportion of cells, suggesting that its mislocalization may reduce and/or impair target recognition. Interestingly, this missense mutation results in a mislocalization of FoxG1 to specific nuclear foci referred to as nuclear speckles, and affects the cyclin-dependent kinase inhibitor p21 CDKN1A expression. Because CDKL5, which is involved in the early-onset variant of Rett syndrome, is also located in these speckles, we suggest that disregulation of the dynamic behaviour of nuclear speckles may functionally link these two proteins, which are both involved in atypical forms of Rett syndrome.
  Human Mutation 02/2011; 32(2):E2026-35. · 5.69 Impact Factor
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  Available from: distrofiamuscular.net

  Article: Angiotensin-converting-enzyme inhibitors versus steroids as first-line drug treatment in Duchenne muscular dystrophy.

  Stéphane Chabrier, Isabelle Desguerre, Mélanie Porte, Claude Payet, François Rivier
  Developmental Medicine & Child Neurology 11/2010; 52(11):1067-8. · 2.92 Impact Factor
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  Available from: Alexis Arzimanoglou

  Article: Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females.

  Christel Depienne, Oriane Trouillard, Delphine Bouteiller, Isabelle Gourfinkel-An, Karine Poirier, François Rivier, Patrick Berquin, Rima Nabbout, Denys Chaigne, Dominique Steschenko, [......], Marie Bru, Brigitte Gilbert-Dussardier, Agathe Roubertie, Anna Kaminska, Sandra Whalen, Cyril Mignot, Stéphanie Baulac, Gaetan Lesca, Alexis Arzimanoglou, Eric LeGuern
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  ABSTRACT: Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation.
  Human Mutation 11/2010; 32(1):E1959-75. · 5.69 Impact Factor
• Article: Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood.

  Laurent Abel, Sabine Plancoulaine, Emmanuelle Jouanguy, Shen-Ying Zhang, Nora Mahfoufi, Nathalie Nicolas, Vanessa Sancho-Shimizu, Alexandre Alcaïs, Yiqi Guo, Annabelle Cardon, [......], Bénédicte Héron, Leila Lazaro, Josette Mancini, Jean-Michel Pedespan, François Rivier, Louis Vallée, Pierre Lebon, Flore Rozenberg, Jean-Laurent Casanova, Marc Tardieu
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  ABSTRACT: To test the hypothesis that predisposition to childhood herpes simplex virus (HSV) type 1 encephalitis (HSE) may be determined in part by human genetic factors. A genetic epidemiologic survey of childhood HSE (onset at age 3 months to 15 years) over a 20-year period (1985-2004) was conducted throughout France (comprising 29 university hospital neuropediatric centers). A total of 85 children fulfilled the diagnostic criteria for inclusion. Family and personal histories were obtained by face-to-face interview for 51 patients. No familial cases of HSE were identified in our survey; however, a high proportion (20%) of the children interviewed had a relevant family history: parental consanguinity (12% of patients), early-onset herpetic keratitis in a first-degree relative (6%), or both (2%). The narrow window of high susceptibility to HSE before age 3 years (62% of patients) further indicates that predisposition to HSE is tightly age-dependent. This survey suggests that childhood HSE, although sporadic, may result from Mendelian predisposition (from autosomal recessive susceptibility in particular), at least in some children. There likely is incomplete penetrance, however, which may reflect, at least in part, the impact of age at the time of HSV-1 infection.
  The Journal of pediatrics 10/2010; 157(4):623-9, 629.e1. · 4.02 Impact Factor
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  Available from: Thierry Kuntzer

  Article: Early onset collagen VI myopathies: Genetic and clinical correlations.

  Laura Briñas, Pascale Richard, Susana Quijano-Roy, Corine Gartioux, Céline Ledeuil, Emmanuelle Lacène, Samira Makri, Ana Ferreiro, Svetlana Maugenre, Haluk Topaloglu, [......], Tanya Stojkovic, Ana Lía Taratuto, Fabiana Lubieniecki, Soledad Monges, Christine Tranchant, Louis Viollet, Norma B Romero, Brigitte Estournet, Pascale Guicheney, Valérie Allamand
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  ABSTRACT: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations. Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA. ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation). This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials.
  Annals of Neurology 10/2010; 68(4):511-20. · 11.09 Impact Factor
• Article: Ventilatory parameters and maximal respiratory pressure changes with age in Duchenne muscular dystrophy patients.

  Jerome Gayraud, Michele Ramonatxo, François Rivier, Véronique Humberclaude, Basil Petrof, Stefan Matecki
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  ABSTRACT: The aim of this longitudinal study was to precise, in children with Duchenne muscular dystrophy, the respective functional interest of ventilatory parameters (Vital capacity, total lung capacity and forced expiratory volume in one second [FEV(1)]) in comparison to maximal inspiratory pressure (Pimax) during growth. In ten boys the mean age of 9.1 +/- 1 years) to mean age of 16 +/- 1.4 years followed over a period of 7 years, we found that: (1) ventilatory parameters expressed in percentage of predicted value, after a normal ascending phase, start to decrease between 11 and 12 years, (2) Pimax presented only a decreasing phase since the beginning of the study and thus was already at 67% of predicted value at 12 years while ventilatory parameters was still normal, (3) after 12 years the mean slopes of decrease per year of vital capacity and FEV1 were higher (10.7 and 10.4%) than that of Pimax (6.9%), (4) at 15 years mean values of vital capacity and FEV1 (53.3 and 49.5% of predicted values) was simlar to that of Pimax (48.3%). In conclusion, if at early stages of the disease, Pimax is a more reliable index of respiratory impaiment than ventilatory parameters, the follow-up of ventilatory parameters, when they start to decrease, is a better indicator of disease progression and, at advanced stages they provided same information about the functional impact of disease.
  Pediatric Pulmonology 06/2010; 45(6):552-9. · 2.53 Impact Factor
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  Available from: Bernard Echenne

  Article: Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression.

  Fatma Daoud, Nathalie Angeard, Bénédicte Demerre, Itxaso Martie, Rabah Benyaou, France Leturcq, Mireille Cossée, Nathalie Deburgrave, Yoann Saillour, Sylvie Tuffery, [......], Michèle Mayer, Isabelle Desguerre, Brigitte Estournet, Christian Réveillère, Penisson-Besnier, Jean Marie Cuisset, Jean Claude Kaplan, Delphine Héron, François Rivier, Jamel Chelly
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  ABSTRACT: The presence of variable degrees of cognitive impairment, extending from severe mental retardation to specific deficits, in patients with dystrophinopathies is a well-recognized problem. However, molecular basis underlying mental retardation and its severity remain poorly understood and still a matter of debate. Here, we report one of the largest study based on the comparison of clinical, cognitive, molecular and expression data in a large cohort of 81 patients affected with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) bearing mutations predicted to affect either all dystrophin products, including Dp71 or all dystrophin products, except Dp71. In addition to the consistent data defining molecular basis underlying mental retardation in DMD, we show that BMD patients with MR have mutations that significantly affect Dp71 expression or with mutations located in exons 75 and 76. We also show that mutations upstream to exon 62, with DMD phenotype, predicted to lead to a loss-of-function of all dystrophin products, except Dp71 isoform, are associated, predominantly, with normal or borderline cognitive performances. Altogether, these reliable phenotype-genotype correlations in combination with Dp71 mRNA and protein expression studies, strongly indicate that loss-of-function of all dystrophin products is systematically associated with severe form of MR, and Dp71 deficit is a factor that contributes in the severity of MR and may account for a shift of 2 SD downward of the intelligence quotient.
  Human Molecular Genetics 08/2009; 18(20):3779-94. · 7.64 Impact Factor
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  Available from: Nadia Bahi-Buisson

  Article: Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.

  Christel Depienne, Delphine Bouteiller, Boris Keren, Emmanuel Cheuret, Karine Poirier, Oriane Trouillard, Baya Benyahia, Chloé Quelin, Wassila Carpentier, Sophie Julia, [......], Marie Hélias, Isabelle Py, Serge Rivera, Nadia Bahi-Buisson, Isabelle Gourfinkel-An, Cécile Cazeneuve, Merle Ruberg, Alexis Brice, Rima Nabbout, Eric Leguern
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  ABSTRACT: Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.
  PLoS Genetics 03/2009; 5(2):e1000381. · 8.69 Impact Factor
• Article: Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.

  N Bahi-Buisson, K Poirier, N Boddaert, Y Saillour, L Castelnau, N Philip, G Buyse, L Villard, S Joriot, S Marret, M Bourgeois, H Van Esch, L Lagae, J Amiel, L Hertz-Pannier, A Roubertie, F Rivier, J M Pinard, C Beldjord, J Chelly
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  ABSTRACT: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations. We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia. Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.
  Journal of Medical Genetics 08/2008; 45(10):647-53. · 6.36 Impact Factor
• Article: Monoamine metabolism study in severe, early-onset epilepsy in childhood.

  Bernard Echenne, Agathe Roubertie, Julie Leydet, François Rivier, Georg Friedrich Hoffmann
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  ABSTRACT: To investigate the possible dysfunction of monoamine metabolism in patients with early-onset, epileptic encephalopathies. The CSF dopamine, serotonin and biopterin metabolites were studied in 37 patients with severe, mostly drug-resistant epilepsy. No significant abnormality was found, whatever the type of epilepsy, cryptogenic or symptomatic. The present study failed to demonstrate that dysfunction of the main neurotransmitters pathways is a common phenomenon in children with early-onset, severe epileptic encephalopathy.
  Epileptic disorders: international epilepsy journal with videotape 07/2008; 10(2):130-5. · 1.50 Impact Factor
• Article: Myotonic dystrophy type I in childhood Long-term evolution in patients surviving the neonatal period.

  Bernard Echenne, Aline Rideau, Agathe Roubertie, Guillaume Sébire, François Rivier, Bernard Lemieux
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  ABSTRACT: In a retrospective study, 32 patients with myotonic dystrophy, including congenital (n=17) and infantile/juvenile forms (n=15) were studied during a long follow-up lasting 7-28 years (median: 17 years). The clinical presentation was extremely variable; however, a continuum did exist between severe and less severe congenital forms, and later-onset forms, without genotype-phenotype correlation. We observed some unusual presentations, such as 3 cases of isolated club-feet during the neonatal period, and 7 patients (23%) with a completely isolated mental deficiency, language delay and school failure, who only completed the clinical picture several years later. Wechsler scale testing was performed in all cases, and repeated with 8 patients. It demonstrated a decrease in intellectual abilities in 5 patients, suggesting the possibility of a degenerative cerebral process occurring in these children. This decrease has also been reported in some adult cases. This study illustrates the extremely heterogeneous clinical presentation of myotonic dystrophy in childhood.
  European Journal of Paediatric Neurology 06/2008; 12(3):210-23. · 2.12 Impact Factor
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  Available from: Dominique Mornet

  Article: Biochemical properties of gastrokine-1 purified from chicken gizzard smooth muscle.

  Karim Hnia, Cécile Notarnicola, Pascal de Santa Barbara, Gérald Hugon, François Rivier, Dalila Laoudj-Chenivesse, Dominique Mornet
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  ABSTRACT: The potential role and function of gastrokine-1 (GNK1) in smooth muscle cells is investigated in this work by first establishing a preparative protocol to obtain this native protein from freshly dissected chicken gizzard. Some unexpected biochemical properties of gastrokine-1 were deduced by producing specific polyclonal antibody against the purified protein. We focused on the F-actin interaction with gastrokine-1 and the potential role and function in smooth muscle contractile properties. GNK1 is thought to provide mucosal protection in the superficial gastric epithelium. However, the actual role of gastrokine-1 with regards to its known decreased expression in gastric cancer is still unknown. Recently, trefoil factors (TFF) were reported to have important roles in gastric epithelial regeneration and cell turnover, and could be involved in GNK1 interactions. The aim of this study was to evaluate the role and function of GNK1 in smooth muscle cells. From fresh chicken gizzard smooth muscle, an original purification procedure was used to purify a heat soluble 20 kDa protein that was sequenced and found to correspond to the gastrokine-1 protein sequence containing one BRICHOS domain and at least two or possibly three transmembrane regions. The purified protein was used to produce polyclonal antibody and highlighted the smooth muscle cell distribution and F-actin association of GNK1 through a few different methods. Altogether our data illustrate a broader distribution of gastrokine-1 in smooth muscle than only in the gastrointestinal epithelium, and the specific interaction with F-actin highlights and suggests a new role and function of GNK1 within smooth muscle cells. A potential role via TFF interaction in cell-cell adhesion and assembly of actin stress fibres is discussed.
  PLoS ONE 02/2008; 3(12):e3854. · 4.09 Impact Factor
• Article: Effect of beta-Dystroglycan Processing on Utrophin / DP116 Anchorage in Normal and MDX Mouse Schwann Cell Membrane

  Karim Hnia, Gérald Hugon, Ahmed Masmoudi, Jacques Mercier, François Rivier, Dominique Jean-Marie Mornet
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  ABSTRACT: In the peripheral nervous system, utrophin and the short dystrophin isoform (Dp116) are co-localized at the outermost layer of the myelin sheath of nerve fibers; together with the dystroglycan complex. In peripheral nerve, matrix metalloproteinase (MMP) creates a 30 kDa fragment of beta-dystroglycan, leading to a disruption of the link between the extracellular matrix and the cell membrane. Here we asked if the processing of the beta-dystroglycan could influence the anchorage of Dp116 or/and utrophin in normal and mdx Schwann cell membrane. We showed that MMP-9 was more activated in mdx nerve than in wild-type one. This activation leads to an accumulation of the 30 kDa beta-dystroglycan isoform and have an impact on the anchorage of Dp116 and utrophin isoforms in mdx Schwann cells membrane. Our results showed that Dp116 had greater affinity to the full length form of beta-dystroglycan than the 30 kDa form. Moreover, we showed for the first time that the short isoform of utrophin (Up71) was over-expressed in mdx Schwann cells compared to wild-type. In addition, this utrophin isoform (Up71) seems to have greater affinity to the 30 kDa beta-dystroglycan which could explain a more stabilization of this 30 kDa at the membrane compartment. Our results highlight the potential participation of the short utrophin isoform and the cleaved form of beta-dystroglycan in mdx Schwann cell membrane architecture.
  05/2007;