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Dive into the research topics where Stanislas Lyonnet is active.

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Featured researches published by Stanislas Lyonnet.


Nature | 2008

Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma

Isabelle Janoueix-Lerosey; Delphine Lequin; Laurence Brugières; Agnès Ribeiro; Loïc de Pontual; Valérie Combaret; Virginie Raynal; Alain Puisieux; Gudrun Schleiermacher; Gaëlle Pierron; Dominique Valteau-Couanet; Thierry Frebourg; Jean Michon; Stanislas Lyonnet; Jeanne Amiel; Olivier Delattre

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.


Nature Genetics | 2011

Germline deletion of the miR-17 ∼ 92 cluster causes skeletal and growth defects in humans

Loïc de Pontual; Evelyn Yao; Patrick Callier; Laurence Faivre; Valérie Drouin; Sandra Cariou; Arie van Haeringen; David Geneviève; Alice Goldenberg; Myriam Oufadem; Sylvie Manouvrier; Arnold Munnich; Joana A. Vidigal; Michel Vekemans; Stanislas Lyonnet; Alexandra Henrion-Caude; Andrea Ventura; Jeanne Amiel

MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.


Journal of Medical Genetics | 2010

Molecular analysis of pericentrin gene ( PCNT ) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPD II) families

M. Willems; D Geneviève; G Borck; Clarisse Baumann; G. Baujat; Eric Bieth; C Farra; Marion Gerard; Delphine Héron; Bruno Leheup; M. Le Merrer; Stanislas Lyonnet; Dominique Martin-Coignard; Michèle Mathieu; Christel Thauvin-Robinet; A Verloes; Laurence Colleaux; Arnold Munnich; Valérie Cormier-Daire

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II, MIM 210720) and Seckel syndrome (SCKL, MIM 210600) belong to the primordial dwarfism group characterised by intrauterine growth retardation, severe proportionate short stature, and pronounced microcephaly. MOPD II is distinct from SCKL by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Seckel syndrome is associated with defective ATR dependent DNA damage signalling. In 2008, loss-of-function mutations in the pericentrin gene (PCNT) have been identified in 28 patients, including 3 SCKL and 25 MOPDII cases. This gene encodes a centrosomal protein which plays a key role in the organisation of mitotic spindles. The aim of this study was to analyse PCNT in a large series of SCKL-MOPD II cases to further define the clinical spectrum associated with PCNT mutations. Among 18 consanguineous families (13 SCKL and 5 MOPDII) and 6 isolated cases (3 SCKL and 3 MOPD II), 13 distinct mutations were identified in 5/16 SCKL and 8/8 MOPDII including five stop mutations, five frameshift mutations, two splice site mutations, and one apparent missense mutation affecting the last base of exon 19. Moreover, we demonstrated that this latter mutation leads to an abnormal splicing with a predicted premature termination of translation. The clinical analysis of the 5 SCKL cases with PCNT mutations showed that they all presented minor skeletal changes and clinical features compatible with MOPDII diagnosis. It is therefore concluded that, despite variable severity, MOPDII is a genetically homogeneous condition due to loss-of-function of pericentrin.


American Journal of Human Genetics | 2013

ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

Lucas Fares-Taie; Sylvie Gerber; Nicolas Chassaing; Jill Clayton-Smith; Sylvain Hanein; Eduardo Silva; Margaux Serey; Valérie Serre; Xavier Gerard; Clarisse Baumann; Ghislaine Plessis; Bénédicte Demeer; Lionel Bretillon; Christine Bole; Patrick Nitschke; Arnold Munnich; Stanislas Lyonnet; Patrick Calvas; Josseline Kaplan; Nicola Ragge; Jean-Michel Rozet

Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans.


Human Molecular Genetics | 2014

Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects

Annie Laquerrière; Jérome Maluenda; Adrien Camus; Laura Fontenas; Klaus Dieterich; Flora Nolent; Jié Zhou; Nicole Monnier; Philippe Latour; Damien Gentil; Delphine Héron; Isabelle Desguerres; Pierre Landrieu; Claire Beneteau; Benoit Delaporte; Céline Bellesme; Clarisse Baumann; Yline Capri; Alice Goldenberg; Stanislas Lyonnet; Dominique Bonneau; Brigitte Estournet; Susana Quijano-Roy; Christine Francannet; Sylvie Odent; Marie-Hélène Saint-Frison; Sabine Sigaudy; Dominique Figarella-Branger; Antoinette Gelot; Jean-Marie Mussini

Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing (WES) were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underlies saltatory conduction of action potentials along the myelinated axons, an important process for neuronal function. A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.


Human Genetics | 2014

Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form.

Julie Salomon; Olivier Goulet; Danielle Canioni; Nicole Brousse; Julie Lemale; P. Tounian; Aurore Coulomb; Evelyne Marinier; Jean-Pierre Hugot; Frank M. Ruemmele; Jean-Louis Dufier; O. Roche; C. Bodemer; Virginie Colomb; C. Talbotec; Florence Lacaille; Florence Campeotto; Nadine Cerf-Bensussan; Andreas R. Janecke; Thomas Mueller; Sibylle Koletzko; Jean-Paul Bonnefont; Stanislas Lyonnet; Arnold Munnich; Françoise Poirier; Asma Smahi

Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73xa0%) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21xa0%) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (pxa0<xa010−4) and, for half of them, with choanal atresia (pxa0<xa010−4). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556-14A>G (abnormal splicing) was significantly associated with a better outcome (pxa0=xa00.032) with milder PN dependency to weaning in some cases. Finally, four patients (7xa0%) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.


American Journal of Human Genetics | 2016

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.

Sylvie Gerber; Kamil J. Alzayady; Lydie Burglen; Valentina Marchesin; O. Roche; Marlène Rio; Benoit Funalot; Raphael Calmon; Alexandra Durr; Vera Lúcia Gil-da-Silva-Lopes; Maria Fernanda Ribeiro Bittar; Christophe Orssaud; Bénédicte Héron; Edward Ayoub; Patrick Berquin; Nadia Bahi-Buisson; Christine Bole; Cécile Masson; Arnold Munnich; Matias Simons; Marion Delous; Hélène Dollfus; Nathalie Boddaert; Stanislas Lyonnet; Josseline Kaplan; Patrick Calvas; David I. Yule; Jean-Michel Rozet; Lucas Fares Taie

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.


Human Mutation | 2016

Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2.

Nina Bögershausen; Vincent Gatinois; Vera Riehmer; Hülya Kayserili; Jutta Becker; Michaela Thoenes; Pelin Ozlem Simsek-Kiper; Mouna Barat-Houari; Nursel Elcioglu; Dagmar Wieczorek; Sigrid Tinschert; Guillaume Sarrabay; Tim M. Strom; Aurelie Fabre; Gareth Baynam; Elodie Sanchez; Gudrun Nürnberg; Umut Altunoglu; Yline Capri; Bertrand Isidor; Didier Lacombe; Carole Corsini; Valérie Cormier-Daire; Damien Sanlaville; Fabienne Giuliano; Kim-Hanh Le Quan Sang; Honorine Kayirangwa; Peter Nürnberg; Thomas Meitinger; Koray Boduroglu

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up‐to‐date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well‐defined X‐linked KS type 2, and comment on phenotype–genotype correlations as well as sex‐specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki‐like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.


Human Mutation | 2015

Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Frédéric Brioude; Irène Netchine; Françoise Praz; Marilyne Le Jule; Claire Calmel; Didier Lacombe; Martin Catala; Sylvie Odent; Bertrand Isidor; Stanislas Lyonnet; Sabine Sigaudy; Bruno Leheup; Séverine Audebert-Bellanger; Lydie Burglen; Fabienne Giuliano; Jean-Luc Alessandri; Valérie Cormier-Daire; Fanny Laffargue; Sophie Blesson; Isabelle Coupier; James Lespinasse; Patricia Blanchet; Odile Boute; Clarisse Baumann; Michel Polak; Bérénice Doray; Alain Verloes; Géraldine Viot; Yves Le Bouc; Sylvie Rossignol

Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.


American Journal of Medical Genetics Part A | 2010

Paternal uniparental isodisomy of chromosome 6 causing a complex syndrome including complete IFN‐γ receptor 1 deficiency

Carolina Prando; Stéphanie Boisson-Dupuis; Audrey V. Grant; Xiao-Fei Kong; Jacinta Bustamante; Jacqueline Feinberg; Ariane Chapgier; Yoann Rose; Lucile Jannière; Elena Rizzardi; Qiuping Zhang; Catherine M. Shanahan; Louis Viollet; Stanislas Lyonnet; Laurent Abel; Jean-Laurent Casanova

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency associated with clinical disease caused by weakly virulent mycobacterial species. Interferon gamma receptor 1 (IFN‐γR1) deficiency is a genetic etiology of MSMD. We describe the clinical and genetic features of a 7‐year‐old Italian boy suffering from MSMD associated with a complex phenotype, including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features. The child also developed necrotizing pneumonia caused by Rhodococcus equi. The child is homozygous for a nonsense mutation in exon 3 of IFNGR1 as a result of paternal uniparental disomy (UPD) of the entire chromosome 6. This is the first reported case of uniparental disomy resulting in a complex phenotype including MSMD.

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Jeanne Amiel

Paris Descartes University

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Arnold Munnich

Necker-Enfants Malades Hospital

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Alice Goldenberg

Necker-Enfants Malades Hospital

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Jean-Michel Rozet

Paris Descartes University

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Josseline Kaplan

Paris Descartes University

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Loïc de Pontual

Paris Descartes University

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