Human Molecular Genetics, 2014, Vol. 23, No. 9 doi:10.1093/hmg/ddt618 Advance Access published on December 6, 2013
2279–2289
Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects
1
Pathology Laboratory and NeoVasc Region-Inserm Team ERI28, Institute of Research for Innovation in Biomedicine, University of Rouen, 76031 Rouen, France 2Unite´ Mixte de recherche (UMR)-788, Inserm and 3University Paris 11, 94276 Le Kremlin Biceˆtre, France 4De´partement de Ge´ne´tique, CHU Grenoble, Inserm U-836, Institut des Neurosciences, 38043 Grenoble, France 5Laboratoire de Biochimie et Ge´ne´tique Mole´culaire, CHU Grenoble, 38043 Grenoble, France 6 Service de Neurobiologie and 7Unite´ de Ge´ne´tique Clinique, CHU de Lyon, 69677 Bron, France 8De´partement de Ge´ne´tique, INSERM U-975, CHU Pitie´-Salpeˆtrie`re, 75013 Paris, France 9Unite´ de Neurope´diatrie and 10Service d’Histologie-Embryologie-Cytoge´ne´tique, CHU Necker-Enfants Malades, 75743 Paris, France 11Service de Ge´ne´tique Me´dicale, UMR-1089, Inserm, Universite´ de Nantes, CHU Nantes, 44093 Nantes, France 12Service de Pe´diatrie Ne´onatale and 13Unite´ de Ge´ne´tique Me´dicale et Cytoge´ne´tique, CH Havre, 76083 Le Havre, France 14Service de Neurope´diatrie, CHU Biceˆtre, 94276 Le Kremlin-Biceˆtre, France 15De´partement de Ge´ne´tique and 16Unite´ de Foetopathologie, CHU Robert Debre´, 75935 Paris, France 17Service de Ge´ne´tique, CHU Rouen, Inserm U-1079, 76031 Rouen, France 18Universite´ Paris Descartes- Sorbonne Paris Cite´, Institut Imagine, INSERM U781, APHP NeckerEnfants Malades, 75743 Paris, France 19De´partement de Biochimie et Ge´ne´tique, CHU Angers, 49933 Angers, France 20 UMR CNRS U6214, INSERM U1083, 49933 Angers, France 21Service de Pe´diatrie et Re´animation infantile, Hopital R. Poincare´, 92380 Garches, France 22Unite´ de Ge´ne´tique Me´dicale, CHU Clermont-Ferrand, 63003 Clermont-Ferrand, France 23Service de Ge´ne´tique Clinique, CHU Rennes, UMR6290 IGDR Universite´ Rennes 1, 35203 Rennes, France 24 Service d’Anatomie et de Cytologie Pathologiques, Hopital Argenteuil, 95107 Argenteuil, France 25De´partement de Ge´ne´tique Me´dicale, CHU de La Timone, 13385 Marseille, France 26Service d’Anatomie Pathologique et de Neuropathologie, CHU de la Timone, 13005 Marseille, France 27Service de Neuropathologie and 28Service de Ge´ne´tique et d’Embryologie Me´dicales, Universite´ Paris VI, Hopital Trousseau, 75571 Paris, France 29Service d’Anatomie et de ∗
To whom correspondence should be addressed at: UMR-986, 80 rue du Ge´ne´ral Leclerc, 94276, Le Kremlin-Biceˆtre, France. Tel: +33 149595370; Fax: +33 149591959; Email: [email protected] † Equal contribution. ‡ Present address: UMR-986, Inserm and University Paris 11, 94276 Le Kremlin Biceˆtre, France.
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://hmg.oxfordjournals.org/ at Selcuk University on January 13, 2015
Annie Laque´rriere1, Je´rome Maluenda2,3,{, {, Adrien Camus2,3,{,{, Laura Fontenas2,3, Klaus Dieterich2,4, Flora Nolent2,3,{, Jie´ Zhou2,3, Nicole Monnier5, Philippe Latour6,7, Damien Gentil1, Delphine He´ron8, Isabelle Desguerres9, Pierre Landrieu3, Claire Beneteau11, Benoit Delaporte12, Ce´line Bellesme14, Clarisse Baumann15, Yline Capri15, Alice Goldenberg17, Stanislas Lyonnet18, Dominique Bonneau19,20, Brigitte Estournet21, Susana Quijano-Roy21, Christine Francannet22, Sylvie Odent23, Marie-He´le`ne Saint-Frison24, Sabine Sigaudy25, Dominique Figarella-Branger26, Antoinette Gelot27, Jean-Marie Mussini29, Catherine Lacroix30, Valerie Drouin-Garraud17, MarieClaire Malinge19, Tania Attie´-Bitach18, Bettina Bessieres10, Maryse Bonniere10, Ferechte EnchaRazavi10, Anne-Marie Beaufre`re31, Suonary Khung-Savatovsky16, Marie Jose´ Perez32, Alexandre Vasiljevic33, Sandra Mercier11, Joelle Roume34, Laetitia Trestard35, Pascale Saugier-Veber17, Marie-Pierre Cordier7, Vale´rie Layet13, Marine Legendre36, Adeline Vigouroux-Castera37, Joel Lunardi5, Monica Bayes38, Pierre S. Jouk4, Luc Rigonnot39, Miche`le Granier40, Damien Sternberg41, Josiane Warszawski42, Ivo Gut38, Marie Gonzales28, Marcel Tawk2,3 and Judith Melki2,3,43,{, ∗
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Cytologie Pathologiques, CHU de Nantes, 44093 Nantes, France 30Laboratoire de Neuropathologie, CHU de Biceˆtre, 94276 Le Kremlin-Biceˆtre, France 31Service de pathologie, CHU Clermont-Ferrand, 63001 Clermont-Ferrand, France 32 De´partement Ge´ne´tique, Foetopathologie CHU Montpellier, 34295 Montpellier, France 33Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon, 69677 Bron, France 34Unite´ de Ge´ne´tique Me´dicale, Hopital de Poissy, 78303 Poissy, France 35Unite´ de Ge´ne´tique, Hopital du Belvede`re, 76131 Mont-Saint-Aignan, France 36Service de Ge´ne´tique Clinique, CHU de Poitiers, 86021 Poitiers, France 37Service de Ge´ne´tique Me´dicale, CHU Toulouse, 31059 Toulouse, France 38Centro Nacional de Ana´lisis Geno´mico, Barcelona 080028, Spain 39Service d’Obste´trique, Centre Hospitalier Sud-Francilien (CHSF), 91108 Corbeil Essonnes, France 40Service de Me´decine Ne´onatale, CHSF, 91108 Corbeil Essonnes, France 41Assistance Publique Hoˆpitaux de Paris, Hoˆpitaux Universitaires Pitie´-Salpeˆtrie`re, Service de Biochimie Me´tabolique, 75651 Paris, France 42UMR-1018, Inserm et Universite´ Paris 11, Service d’Epide´miologie-Sante´ Publique, CHU Bicetre, 94276 Le Kremlin-Biceˆtre, France 43AP-HP, Hoˆpital Biceˆtre, Unite´ de Ge´ne´tique Me´dicale, Le Kremlin-Biceˆtre, 94276; CHSF, 91108 Corbeil Essonnes, France Received October 27, 2013; Revised November 21, 2013; Accepted December 3, 2013
INTRODUCTION Arthrogryposis multiplex congenita (AMC) is characterized by congenital contractures of at least two distinct joints of the body. The overall incidence is 1 in 3000 of live births (1,2). Some non-genetic factors may cause AMC, such as mechanical limitation of fetal movements or maternal autoimmune myasthenia. A number of genetic syndromes including AMC phenotype, collectively referred to as syndromic AMC, have been described under several conditions (3,4). Non-syndromic or isolated AMCs are the direct consequence of fetal akinesia/hypokinesia sequence which may lead, in addition to AMCs, to pterygia, lung hypoplasia, diaphragmatic defect or cleft palate. Isolated AMCs are genetically heterogeneous. Mutations of genes encoding components of the neuromuscular junctions (NMJ), including CHRNG (MIM 100730), CHRNA1 (MIM 100690), CHRND (MIM 100720), CHRNB1 (MIM 100710), DOK7 (MIM 610285), RAPSN (MIM 601592) or CHAT (MIM 118490), are responsible for lethal multiple pterygium syndromes, isolated AMC with neonatal myasthenia or Escobar syndrome. Fetal
motor neuron diseases may also result in lethal congenital contractures caused by mutations in GLE1 (MIM 603371), PIP5K1C (MIM 606102) or ERBB3 (MIM 190151) genes. AMC also occasionally occurs in type I spinal muscular atrophy (SMA) caused by mutations of SMN1 (MIM 600354) or congenital SMA linked to TRPV4 mutations (MIM 605427). More recently, mutations of ECEL1 (MIM 605896) have been reported in distal AMC. Congenital myopathies associated with distal AMC may be caused by mutations in TPM2 (MIM 190990), MYH2 (MIM 160740), MYH3 (MIM 160720), MYH8 (MIM 160741), TNNI2 (MIM 191043), TNNT3 (MIM 600692) or MYBPC1 (MIM 160794) genes. Congenital myotonic dystrophy caused by abnormal triplet expansion of the DMPK (MIM 605377) gene, nemalin myopathy linked to ACTA1 (MIM 102610), TPM2 (MIM 190990) or NEB (MIM 161650), minicore myopathy linked to RYR1 mutations (MIM 180901) or more recently SYNE1 mutation (MIM 608441) have all been reported in non-syndromic AMC. Collectively, non-syndromic AMCs include a large spectrum of diseases of motor neurons, NMJs or skeletal muscle.
Downloaded from http://hmg.oxfordjournals.org/ at Selcuk University on January 13, 2015
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 (
2279–2289
Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects
1
Pathology Laboratory and NeoVasc Region-Inserm Team ERI28, Institute of Research for Innovation in Biomedicine, University of Rouen, 76031 Rouen, France 2Unite´ Mixte de recherche (UMR)-788, Inserm and 3University Paris 11, 94276 Le Kremlin Biceˆtre, France 4De´partement de Ge´ne´tique, CHU Grenoble, Inserm U-836, Institut des Neurosciences, 38043 Grenoble, France 5Laboratoire de Biochimie et Ge´ne´tique Mole´culaire, CHU Grenoble, 38043 Grenoble, France 6 Service de Neurobiologie and 7Unite´ de Ge´ne´tique Clinique, CHU de Lyon, 69677 Bron, France 8De´partement de Ge´ne´tique, INSERM U-975, CHU Pitie´-Salpeˆtrie`re, 75013 Paris, France 9Unite´ de Neurope´diatrie and 10Service d’Histologie-Embryologie-Cytoge´ne´tique, CHU Necker-Enfants Malades, 75743 Paris, France 11Service de Ge´ne´tique Me´dicale, UMR-1089, Inserm, Universite´ de Nantes, CHU Nantes, 44093 Nantes, France 12Service de Pe´diatrie Ne´onatale and 13Unite´ de Ge´ne´tique Me´dicale et Cytoge´ne´tique, CH Havre, 76083 Le Havre, France 14Service de Neurope´diatrie, CHU Biceˆtre, 94276 Le Kremlin-Biceˆtre, France 15De´partement de Ge´ne´tique and 16Unite´ de Foetopathologie, CHU Robert Debre´, 75935 Paris, France 17Service de Ge´ne´tique, CHU Rouen, Inserm U-1079, 76031 Rouen, France 18Universite´ Paris Descartes- Sorbonne Paris Cite´, Institut Imagine, INSERM U781, APHP NeckerEnfants Malades, 75743 Paris, France 19De´partement de Biochimie et Ge´ne´tique, CHU Angers, 49933 Angers, France 20 UMR CNRS U6214, INSERM U1083, 49933 Angers, France 21Service de Pe´diatrie et Re´animation infantile, Hopital R. Poincare´, 92380 Garches, France 22Unite´ de Ge´ne´tique Me´dicale, CHU Clermont-Ferrand, 63003 Clermont-Ferrand, France 23Service de Ge´ne´tique Clinique, CHU Rennes, UMR6290 IGDR Universite´ Rennes 1, 35203 Rennes, France 24 Service d’Anatomie et de Cytologie Pathologiques, Hopital Argenteuil, 95107 Argenteuil, France 25De´partement de Ge´ne´tique Me´dicale, CHU de La Timone, 13385 Marseille, France 26Service d’Anatomie Pathologique et de Neuropathologie, CHU de la Timone, 13005 Marseille, France 27Service de Neuropathologie and 28Service de Ge´ne´tique et d’Embryologie Me´dicales, Universite´ Paris VI, Hopital Trousseau, 75571 Paris, France 29Service d’Anatomie et de ∗
To whom correspondence should be addressed at: UMR-986, 80 rue du Ge´ne´ral Leclerc, 94276, Le Kremlin-Biceˆtre, France. Tel: +33 149595370; Fax: +33 149591959; Email: [email protected] † Equal contribution. ‡ Present address: UMR-986, Inserm and University Paris 11, 94276 Le Kremlin Biceˆtre, France.
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://hmg.oxfordjournals.org/ at Selcuk University on January 13, 2015
Annie Laque´rriere1, Je´rome Maluenda2,3,{, {, Adrien Camus2,3,{,{, Laura Fontenas2,3, Klaus Dieterich2,4, Flora Nolent2,3,{, Jie´ Zhou2,3, Nicole Monnier5, Philippe Latour6,7, Damien Gentil1, Delphine He´ron8, Isabelle Desguerres9, Pierre Landrieu3, Claire Beneteau11, Benoit Delaporte12, Ce´line Bellesme14, Clarisse Baumann15, Yline Capri15, Alice Goldenberg17, Stanislas Lyonnet18, Dominique Bonneau19,20, Brigitte Estournet21, Susana Quijano-Roy21, Christine Francannet22, Sylvie Odent23, Marie-He´le`ne Saint-Frison24, Sabine Sigaudy25, Dominique Figarella-Branger26, Antoinette Gelot27, Jean-Marie Mussini29, Catherine Lacroix30, Valerie Drouin-Garraud17, MarieClaire Malinge19, Tania Attie´-Bitach18, Bettina Bessieres10, Maryse Bonniere10, Ferechte EnchaRazavi10, Anne-Marie Beaufre`re31, Suonary Khung-Savatovsky16, Marie Jose´ Perez32, Alexandre Vasiljevic33, Sandra Mercier11, Joelle Roume34, Laetitia Trestard35, Pascale Saugier-Veber17, Marie-Pierre Cordier7, Vale´rie Layet13, Marine Legendre36, Adeline Vigouroux-Castera37, Joel Lunardi5, Monica Bayes38, Pierre S. Jouk4, Luc Rigonnot39, Miche`le Granier40, Damien Sternberg41, Josiane Warszawski42, Ivo Gut38, Marie Gonzales28, Marcel Tawk2,3 and Judith Melki2,3,43,{, ∗
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Human Molecular Genetics, 2014, Vol. 23, No. 9
Cytologie Pathologiques, CHU de Nantes, 44093 Nantes, France 30Laboratoire de Neuropathologie, CHU de Biceˆtre, 94276 Le Kremlin-Biceˆtre, France 31Service de pathologie, CHU Clermont-Ferrand, 63001 Clermont-Ferrand, France 32 De´partement Ge´ne´tique, Foetopathologie CHU Montpellier, 34295 Montpellier, France 33Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon, 69677 Bron, France 34Unite´ de Ge´ne´tique Me´dicale, Hopital de Poissy, 78303 Poissy, France 35Unite´ de Ge´ne´tique, Hopital du Belvede`re, 76131 Mont-Saint-Aignan, France 36Service de Ge´ne´tique Clinique, CHU de Poitiers, 86021 Poitiers, France 37Service de Ge´ne´tique Me´dicale, CHU Toulouse, 31059 Toulouse, France 38Centro Nacional de Ana´lisis Geno´mico, Barcelona 080028, Spain 39Service d’Obste´trique, Centre Hospitalier Sud-Francilien (CHSF), 91108 Corbeil Essonnes, France 40Service de Me´decine Ne´onatale, CHSF, 91108 Corbeil Essonnes, France 41Assistance Publique Hoˆpitaux de Paris, Hoˆpitaux Universitaires Pitie´-Salpeˆtrie`re, Service de Biochimie Me´tabolique, 75651 Paris, France 42UMR-1018, Inserm et Universite´ Paris 11, Service d’Epide´miologie-Sante´ Publique, CHU Bicetre, 94276 Le Kremlin-Biceˆtre, France 43AP-HP, Hoˆpital Biceˆtre, Unite´ de Ge´ne´tique Me´dicale, Le Kremlin-Biceˆtre, 94276; CHSF, 91108 Corbeil Essonnes, France Received October 27, 2013; Revised November 21, 2013; Accepted December 3, 2013
INTRODUCTION Arthrogryposis multiplex congenita (AMC) is characterized by congenital contractures of at least two distinct joints of the body. The overall incidence is 1 in 3000 of live births (1,2). Some non-genetic factors may cause AMC, such as mechanical limitation of fetal movements or maternal autoimmune myasthenia. A number of genetic syndromes including AMC phenotype, collectively referred to as syndromic AMC, have been described under several conditions (3,4). Non-syndromic or isolated AMCs are the direct consequence of fetal akinesia/hypokinesia sequence which may lead, in addition to AMCs, to pterygia, lung hypoplasia, diaphragmatic defect or cleft palate. Isolated AMCs are genetically heterogeneous. Mutations of genes encoding components of the neuromuscular junctions (NMJ), including CHRNG (MIM 100730), CHRNA1 (MIM 100690), CHRND (MIM 100720), CHRNB1 (MIM 100710), DOK7 (MIM 610285), RAPSN (MIM 601592) or CHAT (MIM 118490), are responsible for lethal multiple pterygium syndromes, isolated AMC with neonatal myasthenia or Escobar syndrome. Fetal
motor neuron diseases may also result in lethal congenital contractures caused by mutations in GLE1 (MIM 603371), PIP5K1C (MIM 606102) or ERBB3 (MIM 190151) genes. AMC also occasionally occurs in type I spinal muscular atrophy (SMA) caused by mutations of SMN1 (MIM 600354) or congenital SMA linked to TRPV4 mutations (MIM 605427). More recently, mutations of ECEL1 (MIM 605896) have been reported in distal AMC. Congenital myopathies associated with distal AMC may be caused by mutations in TPM2 (MIM 190990), MYH2 (MIM 160740), MYH3 (MIM 160720), MYH8 (MIM 160741), TNNI2 (MIM 191043), TNNT3 (MIM 600692) or MYBPC1 (MIM 160794) genes. Congenital myotonic dystrophy caused by abnormal triplet expansion of the DMPK (MIM 605377) gene, nemalin myopathy linked to ACTA1 (MIM 102610), TPM2 (MIM 190990) or NEB (MIM 161650), minicore myopathy linked to RYR1 mutations (MIM 180901) or more recently SYNE1 mutation (MIM 608441) have all been reported in non-syndromic AMC. Collectively, non-syndromic AMCs include a large spectrum of diseases of motor neurons, NMJs or skeletal muscle.
Downloaded from http://hmg.oxfordjournals.org/ at Selcuk University on January 13, 2015
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 (
