Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

Stephanie Efthymiou; Vincenzo Salpietro; Nancy Malintan; Mallory Poncelet; Yamna Kriouile; Sara Fortuna; Rita De Zorzi; Katelyn Payne; Lindsay B. Henderson; Andrea Cortese; Sateesh Maddirevula; Nadia Alhashmi; Sarah Wiethoff; Mina Ryten; Juan A. Botia; Vincenzo Provitera; Markus Schuelke; Jana Vandrovcova; Laurence Walsh; Erin Torti; Valeria Iodice; Maryam Najafi; Ehsan Ghayoor Karimiani; Reza Maroofian; Karine Siquier-Pernet; Nathalie Boddaert; Pascale De Lonlay; Vincent Cantagrel; Mhammed Aguennouz; Mohamed El Khorassani; Miriam Schmidts; Fowzan S. Alkuraya; Simon Edvardson; Maria Nolano; Jérôme Devaux; Henry Houlden; Stanislav Groppa; Blagovesta Marinova Karashova; Wolfgang Nachbauer; Sylvia Boesch; Larissa Arning; Dagmar Timmann; Bru Cormand; Belen Pérez-Dueñas; Jatinder S. Goraya; Tipu Sultan; Jun Mine; Daniela Avdjieva; Hadil Kathom; Radka Tincheva; Selina Banu; Mercedes Pineda-Marfa; Pierangelo Veggiotti; Michel D. Ferrari; Arn M.J.M. Van Den Maagdenberg; Alberto Verrotti; Giangluigi Marseglia; Salvatore Savasta; Mayte García-Silva; Alfons Macaya Ruiz; Barbara Garavaglia; Eugenia Borgione; Simona Portaro; Benigno Monteagudo Sanchez; Richard Boles; Savvas Papacostas; Michail Vikelis; James Rothman; Dimitri Kullmann; Eleni Zamba Papanicolaou; Efthymios Dardiotis; Shazia Maqbool; Shahnaz Ibrahim; Salman Kirmani; Nuzhat Noureen Rana; Osama Atawneh; Shen Yang Lim; Farooq Shaikh; George Koutsis; Marianthi Breza; Salvatore Mangano; Carmela Scuderi; Eugenia Borgione; Giovanna Morello; Tanya Stojkovic; Massimo Zollo; Gali Heimer; Yves A. Dauvilliers; Carlo Minetti; Issam Al-Khawaja; Fuad Al-Mutairi; Sherifa Hamed; Menelaos Pipis; Conceicao Bettencourt; Simon Rinaldi

doi:10.1093/brain/awz248

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

Stephanie Efthymiou, Vincenzo Salpietro, Nancy Malintan, Mallory Poncelet, Yamna Kriouile, Sara Fortuna, Rita De Zorzi, Katelyn Payne, Lindsay B. Henderson, Andrea Cortese, Sateesh Maddirevula, Nadia Alhashmi, Sarah Wiethoff, Mina Ryten, Juan A. Botia, Vincenzo Provitera, Markus Schuelke, Jana Vandrovcova, Laurence Walsh, Erin TortiValeria Iodice, Maryam Najafi, Ehsan Ghayoor Karimiani, Reza Maroofian, Karine Siquier-Pernet, Nathalie Boddaert, Pascale De Lonlay, Vincent Cantagrel, Mhammed Aguennouz, Mohamed El Khorassani, Miriam Schmidts, Fowzan S. Alkuraya, Simon Edvardson, Maria Nolano, Jérôme Devaux, Henry Houlden, Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Jatinder S. Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D. Ferrari, Arn M.J.M. Van Den Maagdenberg, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, James Rothman, Dimitri Kullmann, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, Shen Yang Lim, Farooq Shaikh, George Koutsis, Marianthi Breza, Salvatore Mangano, Carmela Scuderi, Eugenia Borgione, Giovanna Morello, Tanya Stojkovic, Massimo Zollo, Gali Heimer, Yves A. Dauvilliers, Carlo Minetti, Issam Al-Khawaja, Fuad Al-Mutairi, Sherifa Hamed, Menelaos Pipis, Conceicao Bettencourt, Simon Rinaldi

Human Development Programme, Medical College, Pakistan

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

55 Citations (Scopus)

Abstract

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

Original language	English
Pages (from-to)	2948-2964
Number of pages	17
Journal	Brain
Volume	142
Issue number	10
DOIs	https://doi.org/10.1093/brain/awz248
Publication status	Published - 1 Oct 2019

Keywords

Neurodevelopment
Neurofascin
Peripheral demyelination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/brain/awz248

Cite this

Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., De Zorzi, R., Payne, K., Henderson, L. B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J. A., Provitera, V., Schuelke, M., Vandrovcova, J., Walsh, L., ... Rinaldi, S. (2019). Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination. Brain, 142(10), 2948-2964. https://doi.org/10.1093/brain/awz248

@article{ced7acd2fa99434eacb944b58f895b1d,

title = "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination",

abstract = "Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.",

keywords = "Neurodevelopment, Neurofascin, Peripheral demyelination",

author = "Stephanie Efthymiou and Vincenzo Salpietro and Nancy Malintan and Mallory Poncelet and Yamna Kriouile and Sara Fortuna and {De Zorzi}, Rita and Katelyn Payne and Henderson, {Lindsay B.} and Andrea Cortese and Sateesh Maddirevula and Nadia Alhashmi and Sarah Wiethoff and Mina Ryten and Botia, {Juan A.} and Vincenzo Provitera and Markus Schuelke and Jana Vandrovcova and Laurence Walsh and Erin Torti and Valeria Iodice and Maryam Najafi and Karimiani, {Ehsan Ghayoor} and Reza Maroofian and Karine Siquier-Pernet and Nathalie Boddaert and {De Lonlay}, Pascale and Vincent Cantagrel and Mhammed Aguennouz and {El Khorassani}, Mohamed and Miriam Schmidts and Alkuraya, {Fowzan S.} and Simon Edvardson and Maria Nolano and J{\'e}r{\^o}me Devaux and Henry Houlden and Stanislav Groppa and Karashova, {Blagovesta Marinova} and Wolfgang Nachbauer and Sylvia Boesch and Larissa Arning and Dagmar Timmann and Bru Cormand and Belen P{\'e}rez-Due{\~n}as and Goraya, {Jatinder S.} and Tipu Sultan and Jun Mine and Daniela Avdjieva and Hadil Kathom and Radka Tincheva and Selina Banu and Mercedes Pineda-Marfa and Pierangelo Veggiotti and Ferrari, {Michel D.} and {Van Den Maagdenberg}, {Arn M.J.M.} and Alberto Verrotti and Giangluigi Marseglia and Salvatore Savasta and Mayte Garc{\'i}a-Silva and Ruiz, {Alfons Macaya} and Barbara Garavaglia and Eugenia Borgione and Simona Portaro and Sanchez, {Benigno Monteagudo} and Richard Boles and Savvas Papacostas and Michail Vikelis and James Rothman and Dimitri Kullmann and Papanicolaou, {Eleni Zamba} and Efthymios Dardiotis and Shazia Maqbool and Shahnaz Ibrahim and Salman Kirmani and Rana, {Nuzhat Noureen} and Osama Atawneh and Lim, {Shen Yang} and Farooq Shaikh and George Koutsis and Marianthi Breza and Salvatore Mangano and Carmela Scuderi and Eugenia Borgione and Giovanna Morello and Tanya Stojkovic and Massimo Zollo and Gali Heimer and Dauvilliers, {Yves A.} and Carlo Minetti and Issam Al-Khawaja and Fuad Al-Mutairi and Sherifa Hamed and Menelaos Pipis and Conceicao Bettencourt and Simon Rinaldi",

note = "Publisher Copyright: {\textcopyright} The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License",

year = "2019",

month = oct,

day = "1",

doi = "10.1093/brain/awz248",

language = "English",

volume = "142",

pages = "2948--2964",

journal = "Brain",

issn = "0006-8950",

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Efthymiou, S, Salpietro, V, Malintan, N, Poncelet, M, Kriouile, Y, Fortuna, S, De Zorzi, R, Payne, K, Henderson, LB, Cortese, A, Maddirevula, S, Alhashmi, N, Wiethoff, S, Ryten, M, Botia, JA, Provitera, V, Schuelke, M, Vandrovcova, J, Walsh, L, Torti, E, Iodice, V, Najafi, M, Karimiani, EG, Maroofian, R, Siquier-Pernet, K, Boddaert, N, De Lonlay, P, Cantagrel, V, Aguennouz, M, El Khorassani, M, Schmidts, M, Alkuraya, FS, Edvardson, S, Nolano, M, Devaux, J, Houlden, H, Groppa, S, Karashova, BM, Nachbauer, W, Boesch, S, Arning, L, Timmann, D, Cormand, B, Pérez-Dueñas, B, Goraya, JS, Sultan, T, Mine, J, Avdjieva, D, Kathom, H, Tincheva, R, Banu, S, Pineda-Marfa, M, Veggiotti, P, Ferrari, MD, Van Den Maagdenberg, AMJM, Verrotti, A, Marseglia, G, Savasta, S, García-Silva, M, Ruiz, AM, Garavaglia, B, Borgione, E, Portaro, S, Sanchez, BM, Boles, R, Papacostas, S, Vikelis, M, Rothman, J, Kullmann, D, Papanicolaou, EZ, Dardiotis, E, Maqbool, S, Ibrahim, S, Kirmani, S, Rana, NN, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Mangano, S, Scuderi, C, Borgione, E, Morello, G, Stojkovic, T, Zollo, M, Heimer, G, Dauvilliers, YA, Minetti, C, Al-Khawaja, I, Al-Mutairi, F, Hamed, S, Pipis, M, Bettencourt, C & Rinaldi, S 2019, 'Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination', Brain, vol. 142, no. 10, pp. 2948-2964. https://doi.org/10.1093/brain/awz248

TY - JOUR

T1 - Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

AU - Efthymiou, Stephanie

AU - Salpietro, Vincenzo

AU - Malintan, Nancy

AU - Poncelet, Mallory

AU - Kriouile, Yamna

AU - Fortuna, Sara

AU - De Zorzi, Rita

AU - Payne, Katelyn

AU - Henderson, Lindsay B.

AU - Cortese, Andrea

AU - Maddirevula, Sateesh

AU - Alhashmi, Nadia

AU - Wiethoff, Sarah

AU - Ryten, Mina

AU - Botia, Juan A.

AU - Provitera, Vincenzo

AU - Schuelke, Markus

AU - Vandrovcova, Jana

AU - Walsh, Laurence

AU - Torti, Erin

AU - Iodice, Valeria

AU - Najafi, Maryam

AU - Karimiani, Ehsan Ghayoor

AU - Maroofian, Reza

AU - Siquier-Pernet, Karine

AU - Boddaert, Nathalie

AU - De Lonlay, Pascale

AU - Cantagrel, Vincent

AU - Aguennouz, Mhammed

AU - El Khorassani, Mohamed

AU - Schmidts, Miriam

AU - Alkuraya, Fowzan S.

AU - Edvardson, Simon

AU - Nolano, Maria

AU - Devaux, Jérôme

AU - Houlden, Henry

AU - Groppa, Stanislav

AU - Karashova, Blagovesta Marinova

AU - Nachbauer, Wolfgang

AU - Boesch, Sylvia

AU - Arning, Larissa

AU - Timmann, Dagmar

AU - Cormand, Bru

AU - Pérez-Dueñas, Belen

AU - Goraya, Jatinder S.

AU - Sultan, Tipu

AU - Mine, Jun

AU - Avdjieva, Daniela

AU - Kathom, Hadil

AU - Tincheva, Radka

AU - Banu, Selina

AU - Pineda-Marfa, Mercedes

AU - Veggiotti, Pierangelo

AU - Ferrari, Michel D.

AU - Van Den Maagdenberg, Arn M.J.M.

AU - Verrotti, Alberto

AU - Marseglia, Giangluigi

AU - Savasta, Salvatore

AU - García-Silva, Mayte

AU - Ruiz, Alfons Macaya

AU - Garavaglia, Barbara

AU - Borgione, Eugenia

AU - Portaro, Simona

AU - Sanchez, Benigno Monteagudo

AU - Boles, Richard

AU - Papacostas, Savvas

AU - Vikelis, Michail

AU - Rothman, James

AU - Kullmann, Dimitri

AU - Papanicolaou, Eleni Zamba

AU - Dardiotis, Efthymios

AU - Maqbool, Shazia

AU - Ibrahim, Shahnaz

AU - Kirmani, Salman

AU - Rana, Nuzhat Noureen

AU - Atawneh, Osama

AU - Lim, Shen Yang

AU - Shaikh, Farooq

AU - Koutsis, George

AU - Breza, Marianthi

AU - Mangano, Salvatore

AU - Scuderi, Carmela

AU - Borgione, Eugenia

AU - Morello, Giovanna

AU - Stojkovic, Tanya

AU - Zollo, Massimo

AU - Heimer, Gali

AU - Dauvilliers, Yves A.

AU - Minetti, Carlo

AU - Al-Khawaja, Issam

AU - Al-Mutairi, Fuad

AU - Hamed, Sherifa

AU - Pipis, Menelaos

AU - Bettencourt, Conceicao

AU - Rinaldi, Simon

N1 - Publisher Copyright: © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

AB - Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

KW - Neurodevelopment

KW - Neurofascin

KW - Peripheral demyelination

UR - http://www.scopus.com/inward/record.url?scp=85072849162&partnerID=8YFLogxK

U2 - 10.1093/brain/awz248

DO - 10.1093/brain/awz248

M3 - Article

C2 - 31501903

AN - SCOPUS:85072849162

SN - 0006-8950

VL - 142

SP - 2948

EP - 2964

JO - Brain

JF - Brain

IS - 10

ER -

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

Abstract

Keywords

UN SDGs

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