Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Autores
Chelban, Viorica; Patel, Nisha; Vandrovcova, Jana; Zanetti, Maria Natalia; Lynch, David S.; Ryten, Mina; Botía, Juan A.; Bello, Oscar Daniel; Tribollet, Eloise; Efthymiou, Stephanie; Davagnanam, Indran; Bashiri, Fahad A.; Wood, Nicholas W.; Rothman, James E.; Alkuraya, Fowzan S.; Houlden, Henry
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.
Fil: Chelban, Viorica. University College London; Estados Unidos. Institute of Emergency Medicine; Moldavia
Fil: Patel, Nisha. King Faisal Specialist Hospital and Research Center; Arabia Saudita
Fil: Vandrovcova, Jana. University College London; Estados Unidos
Fil: Zanetti, Maria Natalia. University College London; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Lynch, David S.. University College London; Estados Unidos
Fil: Ryten, Mina. University College London; Estados Unidos. King’s College London; Reino Unido
Fil: Botía, Juan A.. University College London; Estados Unidos. Universidad de Murcia; España
Fil: Bello, Oscar Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. University College London; Estados Unidos
Fil: Tribollet, Eloise. University College London; Estados Unidos
Fil: Efthymiou, Stephanie. University College London; Estados Unidos
Fil: Davagnanam, Indran. University College London; Estados Unidos
Fil: Bashiri, Fahad A.. King Saud University; Arabia Saudita
Fil: Wood, Nicholas W.. University College London; Estados Unidos. The National Hospital for Neurology and Neurosurgery; Reino Unido
Fil: Rothman, James E.. University of Yale. School of Medicine; Estados Unidos. University College London; Estados Unidos
Fil: Alkuraya, Fowzan S.. King Faisal Specialist Hospital and Research Center; Arabia Saudita. Alfaisal University; Arabia Saudita. King Abdulaziz City for Science and Technology; Arabia Saudita
Fil: Houlden, Henry. The National Hospital for Neurology and Neurosurgery; Reino Unido. University College London; Estados Unidos
Materia
ATAXIA
GENETIC
LEUKODYSTROPHY
NKX6-2
RECESSIVE
SPASTICITY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/183143
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/183143
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mutations in NKX6-2 Cause Progressive Spastic Ataxia and HypomyelinationChelban, VioricaPatel, NishaVandrovcova, JanaZanetti, Maria NataliaLynch, David S.Ryten, MinaBotía, Juan A.Bello, Oscar DanielTribollet, EloiseEfthymiou, StephanieDavagnanam, IndranBashiri, Fahad A.Wood, Nicholas W.Rothman, James E.Alkuraya, Fowzan S.Houlden, HenryATAXIAGENETICLEUKODYSTROPHYNKX6-2RECESSIVESPASTICITYhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.Fil: Chelban, Viorica. University College London; Estados Unidos. Institute of Emergency Medicine; MoldaviaFil: Patel, Nisha. King Faisal Specialist Hospital and Research Center; Arabia SauditaFil: Vandrovcova, Jana. University College London; Estados UnidosFil: Zanetti, Maria Natalia. University College London; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Lynch, David S.. University College London; Estados UnidosFil: Ryten, Mina. University College London; Estados Unidos. King’s College London; Reino UnidoFil: Botía, Juan A.. University College London; Estados Unidos. Universidad de Murcia; EspañaFil: Bello, Oscar Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. University College London; Estados UnidosFil: Tribollet, Eloise. University College London; Estados UnidosFil: Efthymiou, Stephanie. University College London; Estados UnidosFil: Davagnanam, Indran. University College London; Estados UnidosFil: Bashiri, Fahad A.. King Saud University; Arabia SauditaFil: Wood, Nicholas W.. University College London; Estados Unidos. The National Hospital for Neurology and Neurosurgery; Reino UnidoFil: Rothman, James E.. University of Yale. School of Medicine; Estados Unidos. University College London; Estados UnidosFil: Alkuraya, Fowzan S.. King Faisal Specialist Hospital and Research Center; Arabia Saudita. Alfaisal University; Arabia Saudita. King Abdulaziz City for Science and Technology; Arabia SauditaFil: Houlden, Henry. The National Hospital for Neurology and Neurosurgery; Reino Unido. University College London; Estados UnidosCell Press2017-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/183143Chelban, Viorica; Patel, Nisha; Vandrovcova, Jana; Zanetti, Maria Natalia; Lynch, David S.; et al.; Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination; Cell Press; American Journal Of Human Genetics; 100; 6; 6-2017; 969-9770002-92971537-6605CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0002929717301969info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2017.05.009info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:04:09Zoai:ri.conicet.gov.ar:11336/183143instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:04:09.992CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
title Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
spellingShingle Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
Chelban, Viorica
ATAXIA
GENETIC
LEUKODYSTROPHY
NKX6-2
RECESSIVE
SPASTICITY
title_short Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
title_full Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
title_fullStr Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
title_full_unstemmed Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
title_sort Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
dc.creator.none.fl_str_mv Chelban, Viorica
Patel, Nisha
Vandrovcova, Jana
Zanetti, Maria Natalia
Lynch, David S.
Ryten, Mina
Botía, Juan A.
Bello, Oscar Daniel
Tribollet, Eloise
Efthymiou, Stephanie
Davagnanam, Indran
Bashiri, Fahad A.
Wood, Nicholas W.
Rothman, James E.
Alkuraya, Fowzan S.
Houlden, Henry
author Chelban, Viorica
author_facet Chelban, Viorica
Patel, Nisha
Vandrovcova, Jana
Zanetti, Maria Natalia
Lynch, David S.
Ryten, Mina
Botía, Juan A.
Bello, Oscar Daniel
Tribollet, Eloise
Efthymiou, Stephanie
Davagnanam, Indran
Bashiri, Fahad A.
Wood, Nicholas W.
Rothman, James E.
Alkuraya, Fowzan S.
Houlden, Henry
author_role author
author2 Patel, Nisha
Vandrovcova, Jana
Zanetti, Maria Natalia
Lynch, David S.
Ryten, Mina
Botía, Juan A.
Bello, Oscar Daniel
Tribollet, Eloise
Efthymiou, Stephanie
Davagnanam, Indran
Bashiri, Fahad A.
Wood, Nicholas W.
Rothman, James E.
Alkuraya, Fowzan S.
Houlden, Henry
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ATAXIA
GENETIC
LEUKODYSTROPHY
NKX6-2
RECESSIVE
SPASTICITY
topic ATAXIA
GENETIC
LEUKODYSTROPHY
NKX6-2
RECESSIVE
SPASTICITY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.
Fil: Chelban, Viorica. University College London; Estados Unidos. Institute of Emergency Medicine; Moldavia
Fil: Patel, Nisha. King Faisal Specialist Hospital and Research Center; Arabia Saudita
Fil: Vandrovcova, Jana. University College London; Estados Unidos
Fil: Zanetti, Maria Natalia. University College London; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Lynch, David S.. University College London; Estados Unidos
Fil: Ryten, Mina. University College London; Estados Unidos. King’s College London; Reino Unido
Fil: Botía, Juan A.. University College London; Estados Unidos. Universidad de Murcia; España
Fil: Bello, Oscar Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. University College London; Estados Unidos
Fil: Tribollet, Eloise. University College London; Estados Unidos
Fil: Efthymiou, Stephanie. University College London; Estados Unidos
Fil: Davagnanam, Indran. University College London; Estados Unidos
Fil: Bashiri, Fahad A.. King Saud University; Arabia Saudita
Fil: Wood, Nicholas W.. University College London; Estados Unidos. The National Hospital for Neurology and Neurosurgery; Reino Unido
Fil: Rothman, James E.. University of Yale. School of Medicine; Estados Unidos. University College London; Estados Unidos
Fil: Alkuraya, Fowzan S.. King Faisal Specialist Hospital and Research Center; Arabia Saudita. Alfaisal University; Arabia Saudita. King Abdulaziz City for Science and Technology; Arabia Saudita
Fil: Houlden, Henry. The National Hospital for Neurology and Neurosurgery; Reino Unido. University College London; Estados Unidos
description Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.
publishDate 2017
dc.date.none.fl_str_mv 2017-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/183143
Chelban, Viorica; Patel, Nisha; Vandrovcova, Jana; Zanetti, Maria Natalia; Lynch, David S.; et al.; Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination; Cell Press; American Journal Of Human Genetics; 100; 6; 6-2017; 969-977
0002-9297
1537-6605
CONICET Digital
CONICET
url http://hdl.handle.net/11336/183143
identifier_str_mv Chelban, Viorica; Patel, Nisha; Vandrovcova, Jana; Zanetti, Maria Natalia; Lynch, David S.; et al.; Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination; Cell Press; American Journal Of Human Genetics; 100; 6; 6-2017; 969-977
0002-9297
1537-6605
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0002929717301969
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2017.05.009
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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