AustralieFrV1, PubMed, Checkpoint, bibRecord, 001119

Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.

Identifieur interne : 001119 ( PubMed/Checkpoint ); précédent : 001118; suivant : 001120

Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.

Auteurs : Imen Dorboz [France] ; Chiara Aiello [Italie] ; Cas Simons [Australie] ; Robert Thompson Stone [États-Unis] ; Marcello Niceta [Italie] ; Monique Elmaleh [France] ; Mohammad Abuawad [France] ; Diane Doummar [France] ; Alessandro Bruselles [Italie] ; Nicole I. Wolf [Pays-Bas] ; Lorena Travaglini [Italie] ; Odile Boespflug-Tanguy [France] ; Marco Tartaglia [Italie] ; Adeline Vanderver [États-Unis] ; Diana Rodriguez [France] ; Enrico Bertini [Italie]

Source :

Brain : a journal of neurology [ 1460-2156 ] ; 2017.

RBID : pubmed:28969374

Descripteurs français

KwdFr :
- Adolescent, Analyse de mutations d'ADN, Consanguinité, Enfant, Enfant d'âge préscolaire, Femelle, Gènes homéotiques (génétique), Humains, Imagerie par résonance magnétique, Leucoencéphalopathies (anatomopathologie), Leucoencéphalopathies (génétique), Leucoencéphalopathies (imagerie diagnostique), Leucoencéphalopathies (physiopathologie), Modèles moléculaires, Mutation (génétique), Mâle, Potentiels évoqués auditifs du tronc cérébral, Protéines à homéodomaine (génétique), Santé de la famille.
MESH :
- anatomopathologie : Leucoencéphalopathies.
- génétique : Gènes homéotiques, Leucoencéphalopathies, Mutation, Protéines à homéodomaine.
- imagerie diagnostique : Leucoencéphalopathies.
- physiopathologie : Leucoencéphalopathies.
- Adolescent, Analyse de mutations d'ADN, Consanguinité, Enfant, Enfant d'âge préscolaire, Femelle, Humains, Imagerie par résonance magnétique, Modèles moléculaires, Mâle, Potentiels évoqués auditifs du tronc cérébral, Santé de la famille.

English descriptors

KwdEn :
- Adolescent, Child, Child, Preschool, Consanguinity, DNA Mutational Analysis, Evoked Potentials, Auditory, Brain Stem, Family Health, Female, Genes, Homeobox (genetics), Homeodomain Proteins (genetics), Humans, Leukoencephalopathies (diagnostic imaging), Leukoencephalopathies (genetics), Leukoencephalopathies (pathology), Leukoencephalopathies (physiopathology), Magnetic Resonance Imaging, Male, Models, Molecular, Mutation (genetics).
MESH :
- chemical , genetics : Homeodomain Proteins.
- diagnostic imaging : Leukoencephalopathies.
- genetics : Genes, Homeobox, Leukoencephalopathies, Mutation.
- pathology : Leukoencephalopathies.
- physiopathology : Leukoencephalopathies.
- Adolescent, Child, Child, Preschool, Consanguinity, DNA Mutational Analysis, Evoked Potentials, Auditory, Brain Stem, Family Health, Female, Humans, Magnetic Resonance Imaging, Male, Models, Molecular.

Abstract

Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.

DOI: 10.1093/brain/awx207
PubMed: 28969374

Affiliations:

Australie, France, Italie, Pays-Bas, États-Unis
Hollande-Septentrionale, Latium, Île-de-France
Amsterdam, Paris, Rome

Links toward previous steps (curation, corpus...)

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pubmed:28969374

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en">Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.</title>
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<author><name sortKey="Aiello, Chiara" sort="Aiello, Chiara" uniqKey="Aiello C" first="Chiara" last="Aiello">Chiara Aiello</name>
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<author><name sortKey="Boespflug Tanguy, Odile" sort="Boespflug Tanguy, Odile" uniqKey="Boespflug Tanguy O" first="Odile" last="Boespflug-Tanguy">Odile Boespflug-Tanguy</name>
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<front><div type="abstract" xml:lang="en">Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.</div>
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<DateCompleted><Year>2017</Year>
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<Issue>10</Issue>
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<Title>Brain : a journal of neurology</Title>
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<ArticleTitle>Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.</ArticleTitle>
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<Abstract><AbstractText>Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.</AbstractText>
<CopyrightInformation>© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</CopyrightInformation>
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<AffiliationInfo><Affiliation>Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Child Neurology, VU University Medical Center, Amsterdam, and Amsterdam Neuroscience, Amsterdam, The Netherlands.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Neurology, University of Pennsylvania, USA.</Affiliation>
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Serveur d'exploration sur les relations entre la France et l'Australie

Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.

Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.

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