Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Médéric Jeanne; Hélène Demory; Aubin Moutal; Marie Laure Vuillaume; Sophie Blesson; Rose Anne Thépault; Sylviane Marouillat; Judith Halewa; Saskia M. Maas; M. Mahdi Motazacker; Grazia M.S. Mancini; Marjon A. van Slegtenhorst; Avgi Andreou; Helene Cox; Julie Vogt; Jason Laufman; Natella Kostandyan; Davit Babikyan; Miroslava Hancarova; Sarka Bendova; Zdenek Sedlacek; Kimberly A. Aldinger; Elliott H. Sherr; Emanuela Argilli; Eleina M. England; Séverine Audebert-Bellanger; Dominique Bonneau; Estelle Colin; Anne Sophie Denommé-Pichon; Brigitte Gilbert-Dussardier; Bertrand Isidor; Sébastien Küry; Sylvie Odent; Richard Redon; Rajesh Khanna; William B. Dobyns; Stéphane Bézieau; Jérôme Honnorat; Bernhard Lohkamp; Annick Toutain; Frédéric Laumonnier

doi:10.1016/j.ajhg.2021.04.004

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Médéric Jeanne, Hélène Demory, Aubin Moutal, Marie Laure Vuillaume, Sophie Blesson, Rose Anne Thépault, Sylviane Marouillat, Judith Halewa, Saskia M. Maas, M. Mahdi Motazacker, Grazia M.S. Mancini, Marjon A. van Slegtenhorst, Avgi Andreou, Helene Cox, Julie Vogt, Jason Laufman, Natella Kostandyan, Davit Babikyan, Miroslava Hancarova, Sarka BendovaZdenek Sedlacek, Kimberly A. Aldinger, Elliott H. Sherr, Emanuela Argilli, Eleina M. England, Séverine Audebert-Bellanger, Dominique Bonneau, Estelle Colin, Anne Sophie Denommé-Pichon, Brigitte Gilbert-Dussardier, Bertrand Isidor, Sébastien Küry, Sylvie Odent, Richard Redon, Rajesh Khanna, William B. Dobyns, Stéphane Bézieau, Jérôme Honnorat, Bernhard Lohkamp, Annick Toutain, Frédéric Laumonnier

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Original language	English (US)
Pages (from-to)	951-961
Number of pages	11
Journal	American Journal of Human Genetics
Volume	108
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2021.04.004
State	Published - May 6 2021
Externally published	Yes

Bibliographical note

Funding Information:
We thank the participants and families involved in the study. This work was funded by the Association pour le D?veloppement de la Neurog?n?tique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-R?gional (grant no. NCT02136849 to S. B?zieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051).

Funding Information:
We thank the participants and families involved in the study. This work was funded by the Association pour le Développement de la Neurogénétique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-Régional (grant no. NCT02136849 to S. Bézieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051).

Publisher Copyright:
© 2021 American Society of Human Genetics

Keywords

DPYSL5
brain malformation
corpus callosum agenesis
de novo missense variants
dendrite branching
neurodevelopmental disorder
primary neuronal cultures

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10.1016/j.ajhg.2021.04.004

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Jeanne, M., Demory, H., Moutal, A., Vuillaume, M. L., Blesson, S., Thépault, R. A., Marouillat, S., Halewa, J., Maas, S. M., Motazacker, M. M., Mancini, G. M. S., van Slegtenhorst, M. A., Andreou, A., Cox, H., Vogt, J., Laufman, J., Kostandyan, N., Babikyan, D., Hancarova, M., ... Laumonnier, F. (2021). Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities. American Journal of Human Genetics, 108(5), 951-961. https://doi.org/10.1016/j.ajhg.2021.04.004

Jeanne, M, Demory, H, Moutal, A, Vuillaume, ML, Blesson, S, Thépault, RA, Marouillat, S, Halewa, J, Maas, SM, Motazacker, MM, Mancini, GMS, van Slegtenhorst, MA, Andreou, A, Cox, H, Vogt, J, Laufman, J, Kostandyan, N, Babikyan, D, Hancarova, M, Bendova, S, Sedlacek, Z, Aldinger, KA, Sherr, EH, Argilli, E, England, EM, Audebert-Bellanger, S, Bonneau, D, Colin, E, Denommé-Pichon, AS, Gilbert-Dussardier, B, Isidor, B, Küry, S, Odent, S, Redon, R, Khanna, R, Dobyns, WB, Bézieau, S, Honnorat, J, Lohkamp, B, Toutain, A & Laumonnier, F 2021, 'Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities', American Journal of Human Genetics, vol. 108, no. 5, pp. 951-961. https://doi.org/10.1016/j.ajhg.2021.04.004

@article{07b5359d7d1649d4bb989cdfa6fc1a0e,

title = "Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities",

abstract = "The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.",

keywords = "DPYSL5, brain malformation, corpus callosum agenesis, de novo missense variants, dendrite branching, neurodevelopmental disorder, primary neuronal cultures",

author = "M{\'e}d{\'e}ric Jeanne and H{\'e}l{\`e}ne Demory and Aubin Moutal and Vuillaume, {Marie Laure} and Sophie Blesson and Th{\'e}pault, {Rose Anne} and Sylviane Marouillat and Judith Halewa and Maas, {Saskia M.} and Motazacker, {M. Mahdi} and Mancini, {Grazia M.S.} and {van Slegtenhorst}, {Marjon A.} and Avgi Andreou and Helene Cox and Julie Vogt and Jason Laufman and Natella Kostandyan and Davit Babikyan and Miroslava Hancarova and Sarka Bendova and Zdenek Sedlacek and Aldinger, {Kimberly A.} and Sherr, {Elliott H.} and Emanuela Argilli and England, {Eleina M.} and S{\'e}verine Audebert-Bellanger and Dominique Bonneau and Estelle Colin and Denomm{\'e}-Pichon, {Anne Sophie} and Brigitte Gilbert-Dussardier and Bertrand Isidor and S{\'e}bastien K{\"u}ry and Sylvie Odent and Richard Redon and Rajesh Khanna and Dobyns, {William B.} and St{\'e}phane B{\'e}zieau and J{\'e}r{\^o}me Honnorat and Bernhard Lohkamp and Annick Toutain and Fr{\'e}d{\'e}ric Laumonnier",

note = "Funding Information: We thank the participants and families involved in the study. This work was funded by the Association pour le D?veloppement de la Neurog?n?tique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-R?gional (grant no. NCT02136849 to S. B?zieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051). Funding Information: We thank the participants and families involved in the study. This work was funded by the Association pour le D{\'e}veloppement de la Neurog{\'e}n{\'e}tique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-R{\'e}gional (grant no. NCT02136849 to S. B{\'e}zieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051). Publisher Copyright: {\textcopyright} 2021 American Society of Human Genetics",

year = "2021",

month = may,

day = "6",

doi = "10.1016/j.ajhg.2021.04.004",

language = "English (US)",

volume = "108",

pages = "951--961",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

AU - Jeanne, Médéric

AU - Demory, Hélène

AU - Moutal, Aubin

AU - Vuillaume, Marie Laure

AU - Blesson, Sophie

AU - Thépault, Rose Anne

AU - Marouillat, Sylviane

AU - Halewa, Judith

AU - Maas, Saskia M.

AU - Motazacker, M. Mahdi

AU - Mancini, Grazia M.S.

AU - van Slegtenhorst, Marjon A.

AU - Andreou, Avgi

AU - Cox, Helene

AU - Vogt, Julie

AU - Laufman, Jason

AU - Kostandyan, Natella

AU - Babikyan, Davit

AU - Hancarova, Miroslava

AU - Bendova, Sarka

AU - Sedlacek, Zdenek

AU - Aldinger, Kimberly A.

AU - Sherr, Elliott H.

AU - Argilli, Emanuela

AU - England, Eleina M.

AU - Audebert-Bellanger, Séverine

AU - Bonneau, Dominique

AU - Colin, Estelle

AU - Denommé-Pichon, Anne Sophie

AU - Gilbert-Dussardier, Brigitte

AU - Isidor, Bertrand

AU - Küry, Sébastien

AU - Odent, Sylvie

AU - Redon, Richard

AU - Khanna, Rajesh

AU - Dobyns, William B.

AU - Bézieau, Stéphane

AU - Honnorat, Jérôme

AU - Lohkamp, Bernhard

AU - Toutain, Annick

AU - Laumonnier, Frédéric

N1 - Funding Information: We thank the participants and families involved in the study. This work was funded by the Association pour le D?veloppement de la Neurog?n?tique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-R?gional (grant no. NCT02136849 to S. B?zieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051). Funding Information: We thank the participants and families involved in the study. This work was funded by the Association pour le Développement de la Neurogénétique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-Régional (grant no. NCT02136849 to S. Bézieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051). Publisher Copyright: © 2021 American Society of Human Genetics

PY - 2021/5/6

Y1 - 2021/5/6

N2 - The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

AB - The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

KW - DPYSL5

KW - brain malformation

KW - corpus callosum agenesis

KW - de novo missense variants

KW - dendrite branching

KW - neurodevelopmental disorder

KW - primary neuronal cultures

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UR - http://www.scopus.com/inward/citedby.url?scp=85105057003&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2021.04.004

DO - 10.1016/j.ajhg.2021.04.004

M3 - Article

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AN - SCOPUS:85105057003

SN - 0002-9297

VL - 108

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EP - 961

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

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