Mutation spectrum in the large gtpase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

Johann Böhm, Valerie Biancalana, Elizabeth T. DeChene, Marc Bitoun, Christopher R. Pierson, Elise Schaefer, Hatice Karasoy, Melissa A. Dempsey, Fabrice Klein, Nicolas Dondaine, Christine Kretz, Nicolas Haumesser, Claire Poirson, Anne Toussaint, Rebecca S. Greenleaf, Melissa A. Barger, Lane J. Mahoney, Peter B. Kang, Edmar Zanoteli, John Vissing & 48 others Nanna Witting, Andoni Echaniz-Laguna, Carina Wallgren-Pettersson, James Dowling, Luciano Merlini, Anders Oldfors, Lilian Bomme Ousager, Judith Melki, Amanda Krause, Christina Jern, Acary S B Oliveira, Florence Petit, Aurélia Jacquette, Annabelle Chaussenot, David Mowat, Bruno Leheup, Michele Cristofano, Juan José Poza Aldea, Fabrice Michel, Alain Furby, Jose E Barcena Llona, Rudy Van Coster, Enrico Bertini, Jon Andoni Urtizberea, Valérie Drouin-Garraud, Christophe Bé roud, Bernard Prudhon, Melanie Bedford, Katherine Mathews, Lori Ann Hamby Erby, Stephen A. Smith, Jennifer Roggenbuck, Carol A. Crowe, Allison Brennan Spitale, Sheila C. Johal, Anthony A. Amato, Laurie A. Demmer, Jessica Jonas, Basil T. Darras, Thomas D. Bird, Mercy Laurino, Selman I. Welt, Cynthia Trotter, Pascale Guicheney, Soma Das, Jean Louis Mandel, Alan H. Beggs, Jocelyn Laporte

Research output: Contribution to journalArticle

Abstract

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.

Original languageEnglish (US)
Pages (from-to)949-959
Number of pages11
JournalHuman Mutation
Volume33
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Dynamin II
Congenital Structural Myopathies
GTP Phosphohydrolases
Genetic Association Studies
Mutation
Tooth
Membranes
Muscle Weakness
Peripheral Nervous System Diseases
Cytoskeleton
Atrophy
Skeletal Muscle

Keywords

  • ADCNM
  • BIN1
  • Centronuclear myopathy
  • Charcot-marie-tooth neuropathy
  • CMT2M
  • CMTD1B
  • Congenital myopathy
  • Di-CMTB
  • DNM2
  • Endocytosis
  • Hereditary motor and sensory neuropathy type II
  • HMSNII
  • MTM1
  • Myotubular myopathy
  • RYR1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Böhm, J., Biancalana, V., DeChene, E. T., Bitoun, M., Pierson, C. R., Schaefer, E., ... Laporte, J. (2012). Mutation spectrum in the large gtpase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. Human Mutation, 33(6), 949-959. https://doi.org/10.1002/humu.22067

Mutation spectrum in the large gtpase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. / Böhm, Johann; Biancalana, Valerie; DeChene, Elizabeth T.; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.; Barger, Melissa A.; Mahoney, Lane J.; Kang, Peter B.; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Ousager, Lilian Bomme; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S B; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Aldea, Juan José Poza; Michel, Fabrice; Furby, Alain; Llona, Jose E Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; roud, Christophe Bé; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori Ann Hamby; Smith, Stephen A.; Roggenbuck, Jennifer; Crowe, Carol A.; Spitale, Allison Brennan; Johal, Sheila C.; Amato, Anthony A.; Demmer, Laurie A.; Jonas, Jessica; Darras, Basil T.; Bird, Thomas D.; Laurino, Mercy; Welt, Selman I.; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean Louis; Beggs, Alan H.; Laporte, Jocelyn.

In: Human Mutation, Vol. 33, No. 6, 06.2012, p. 949-959.

Research output: Contribution to journalArticle

Böhm, J, Biancalana, V, DeChene, ET, Bitoun, M, Pierson, CR, Schaefer, E, Karasoy, H, Dempsey, MA, Klein, F, Dondaine, N, Kretz, C, Haumesser, N, Poirson, C, Toussaint, A, Greenleaf, RS, Barger, MA, Mahoney, LJ, Kang, PB, Zanoteli, E, Vissing, J, Witting, N, Echaniz-Laguna, A, Wallgren-Pettersson, C, Dowling, J, Merlini, L, Oldfors, A, Ousager, LB, Melki, J, Krause, A, Jern, C, Oliveira, ASB, Petit, F, Jacquette, A, Chaussenot, A, Mowat, D, Leheup, B, Cristofano, M, Aldea, JJP, Michel, F, Furby, A, Llona, JEB, Van Coster, R, Bertini, E, Urtizberea, JA, Drouin-Garraud, V, roud, CB, Prudhon, B, Bedford, M, Mathews, K, Erby, LAH, Smith, SA, Roggenbuck, J, Crowe, CA, Spitale, AB, Johal, SC, Amato, AA, Demmer, LA, Jonas, J, Darras, BT, Bird, TD, Laurino, M, Welt, SI, Trotter, C, Guicheney, P, Das, S, Mandel, JL, Beggs, AH & Laporte, J 2012, 'Mutation spectrum in the large gtpase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy', Human Mutation, vol. 33, no. 6, pp. 949-959. https://doi.org/10.1002/humu.22067
Böhm, Johann ; Biancalana, Valerie ; DeChene, Elizabeth T. ; Bitoun, Marc ; Pierson, Christopher R. ; Schaefer, Elise ; Karasoy, Hatice ; Dempsey, Melissa A. ; Klein, Fabrice ; Dondaine, Nicolas ; Kretz, Christine ; Haumesser, Nicolas ; Poirson, Claire ; Toussaint, Anne ; Greenleaf, Rebecca S. ; Barger, Melissa A. ; Mahoney, Lane J. ; Kang, Peter B. ; Zanoteli, Edmar ; Vissing, John ; Witting, Nanna ; Echaniz-Laguna, Andoni ; Wallgren-Pettersson, Carina ; Dowling, James ; Merlini, Luciano ; Oldfors, Anders ; Ousager, Lilian Bomme ; Melki, Judith ; Krause, Amanda ; Jern, Christina ; Oliveira, Acary S B ; Petit, Florence ; Jacquette, Aurélia ; Chaussenot, Annabelle ; Mowat, David ; Leheup, Bruno ; Cristofano, Michele ; Aldea, Juan José Poza ; Michel, Fabrice ; Furby, Alain ; Llona, Jose E Barcena ; Van Coster, Rudy ; Bertini, Enrico ; Urtizberea, Jon Andoni ; Drouin-Garraud, Valérie ; roud, Christophe Bé ; Prudhon, Bernard ; Bedford, Melanie ; Mathews, Katherine ; Erby, Lori Ann Hamby ; Smith, Stephen A. ; Roggenbuck, Jennifer ; Crowe, Carol A. ; Spitale, Allison Brennan ; Johal, Sheila C. ; Amato, Anthony A. ; Demmer, Laurie A. ; Jonas, Jessica ; Darras, Basil T. ; Bird, Thomas D. ; Laurino, Mercy ; Welt, Selman I. ; Trotter, Cynthia ; Guicheney, Pascale ; Das, Soma ; Mandel, Jean Louis ; Beggs, Alan H. ; Laporte, Jocelyn. / Mutation spectrum in the large gtpase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. In: Human Mutation. 2012 ; Vol. 33, No. 6. pp. 949-959.
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T1 - Mutation spectrum in the large gtpase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

AU - Böhm, Johann

AU - Biancalana, Valerie

AU - DeChene, Elizabeth T.

AU - Bitoun, Marc

AU - Pierson, Christopher R.

AU - Schaefer, Elise

AU - Karasoy, Hatice

AU - Dempsey, Melissa A.

AU - Klein, Fabrice

AU - Dondaine, Nicolas

AU - Kretz, Christine

AU - Haumesser, Nicolas

AU - Poirson, Claire

AU - Toussaint, Anne

AU - Greenleaf, Rebecca S.

AU - Barger, Melissa A.

AU - Mahoney, Lane J.

AU - Kang, Peter B.

AU - Zanoteli, Edmar

AU - Vissing, John

AU - Witting, Nanna

AU - Echaniz-Laguna, Andoni

AU - Wallgren-Pettersson, Carina

AU - Dowling, James

AU - Merlini, Luciano

AU - Oldfors, Anders

AU - Ousager, Lilian Bomme

AU - Melki, Judith

AU - Krause, Amanda

AU - Jern, Christina

AU - Oliveira, Acary S B

AU - Petit, Florence

AU - Jacquette, Aurélia

AU - Chaussenot, Annabelle

AU - Mowat, David

AU - Leheup, Bruno

AU - Cristofano, Michele

AU - Aldea, Juan José Poza

AU - Michel, Fabrice

AU - Furby, Alain

AU - Llona, Jose E Barcena

AU - Van Coster, Rudy

AU - Bertini, Enrico

AU - Urtizberea, Jon Andoni

AU - Drouin-Garraud, Valérie

AU - roud, Christophe Bé

AU - Prudhon, Bernard

AU - Bedford, Melanie

AU - Mathews, Katherine

AU - Erby, Lori Ann Hamby

AU - Smith, Stephen A.

AU - Roggenbuck, Jennifer

AU - Crowe, Carol A.

AU - Spitale, Allison Brennan

AU - Johal, Sheila C.

AU - Amato, Anthony A.

AU - Demmer, Laurie A.

AU - Jonas, Jessica

AU - Darras, Basil T.

AU - Bird, Thomas D.

AU - Laurino, Mercy

AU - Welt, Selman I.

AU - Trotter, Cynthia

AU - Guicheney, Pascale

AU - Das, Soma

AU - Mandel, Jean Louis

AU - Beggs, Alan H.

AU - Laporte, Jocelyn

PY - 2012/6

Y1 - 2012/6

N2 - Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.

AB - Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.

KW - ADCNM

KW - BIN1

KW - Centronuclear myopathy

KW - Charcot-marie-tooth neuropathy

KW - CMT2M

KW - CMTD1B

KW - Congenital myopathy

KW - Di-CMTB

KW - DNM2

KW - Endocytosis

KW - Hereditary motor and sensory neuropathy type II

KW - HMSNII

KW - MTM1

KW - Myotubular myopathy

KW - RYR1

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