A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects
Identifieur interne : 001E81 ( Main/Exploration ); précédent : 001E80; suivant : 001E82A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects
Auteurs : Tobias Warnecke [Allemagne] ; Thomas Duning [Allemagne] ; Anja Schirmacher [Allemagne] ; Siawoosh Mohammadi [Allemagne] ; Wolfram Schwindt [Allemagne] ; Hubertus Lohmann [Allemagne] ; Rainer Dziewas [Allemagne] ; Michael Deppe [Allemagne] ; E. Bernd Ringelstein [Allemagne] ; Peter Young [Allemagne]Source :
- Movement Disorders [ 0885-3185 ] ; 2010-03-15.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
- Adult, Amino Acid Substitution (genetics), Atrophy (genetics), Atrophy (pathology), Brain (pathology), DNA Mutational Analysis, DNA, Recombinant (genetics), Diffusion Magnetic Resonance Imaging, Diffusion tensor imaging, Electrodiagnosis, Female, Genetic Predisposition to Disease, Genetic Testing, Genotype, Hereditary spastic paraplegia, Homozygosity, Human, Humans, Metalloendopeptidases (genetics), Middle Aged, Muscle Fibers, Skeletal (pathology), Mutation, Nervous system diseases, Neural Pathways (pathology), Neuropsychological Tests, Phenotype, Point Mutation (genetics), SPG7, Spastic Paraplegia, Hereditary (genetics), Splice, Splicing, Twins, Dizygotic (genetics), Twins, Monozygotic (genetics), White matter, diffusion tensor imaging, hereditary spastic paraplegia, splice site mutation, white matter damage.
- MESH :
- chemical , genetics : DNA, Recombinant, Metalloendopeptidases.
- genetics : Amino Acid Substitution, Atrophy, Point Mutation, Spastic Paraplegia, Hereditary, Twins, Dizygotic, Twins, Monozygotic.
- pathology : Atrophy, Brain, Muscle Fibers, Skeletal, Neural Pathways.
- Adult, DNA Mutational Analysis, Diffusion Magnetic Resonance Imaging, Electrodiagnosis, Female, Genetic Predisposition to Disease, Genetic Testing, Genotype, Humans, Middle Aged, Neuropsychological Tests, Phenotype.
Abstract
Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult‐onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss‐of‐function of the paraplegin‐AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7‐HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP. © 2010 Movement Disorder Society
Url:
DOI: 10.1002/mds.22949
Affiliations:
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term>
<term>Amino Acid Substitution (genetics)</term>
<term>Atrophy (genetics)</term>
<term>Atrophy (pathology)</term>
<term>Brain (pathology)</term>
<term>DNA Mutational Analysis</term>
<term>DNA, Recombinant (genetics)</term>
<term>Diffusion Magnetic Resonance Imaging</term>
<term>Diffusion tensor imaging</term>
<term>Electrodiagnosis</term>
<term>Female</term>
<term>Genetic Predisposition to Disease</term>
<term>Genetic Testing</term>
<term>Genotype</term>
<term>Hereditary spastic paraplegia</term>
<term>Homozygosity</term>
<term>Human</term>
<term>Humans</term>
<term>Metalloendopeptidases (genetics)</term>
<term>Middle Aged</term>
<term>Muscle Fibers, Skeletal (pathology)</term>
<term>Mutation</term>
<term>Nervous system diseases</term>
<term>Neural Pathways (pathology)</term>
<term>Neuropsychological Tests</term>
<term>Phenotype</term>
<term>Point Mutation (genetics)</term>
<term>SPG7</term>
<term>Spastic Paraplegia, Hereditary (genetics)</term>
<term>Splice</term>
<term>Splicing</term>
<term>Twins, Dizygotic (genetics)</term>
<term>Twins, Monozygotic (genetics)</term>
<term>White matter</term>
<term>diffusion tensor imaging</term>
<term>hereditary spastic paraplegia</term>
<term>splice site mutation</term>
<term>white matter damage</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>DNA, Recombinant</term>
<term>Metalloendopeptidases</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Amino Acid Substitution</term>
<term>Atrophy</term>
<term>Point Mutation</term>
<term>Spastic Paraplegia, Hereditary</term>
<term>Twins, Dizygotic</term>
<term>Twins, Monozygotic</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Atrophy</term>
<term>Brain</term>
<term>Muscle Fibers, Skeletal</term>
<term>Neural Pathways</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adult</term>
<term>DNA Mutational Analysis</term>
<term>Diffusion Magnetic Resonance Imaging</term>
<term>Electrodiagnosis</term>
<term>Female</term>
<term>Genetic Predisposition to Disease</term>
<term>Genetic Testing</term>
<term>Genotype</term>
<term>Humans</term>
<term>Middle Aged</term>
<term>Neuropsychological Tests</term>
<term>Phenotype</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Epissage</term>
<term>Epissure</term>
<term>Homme</term>
<term>Homozygotie</term>
<term>Imagerie du tenseur de diffusion</term>
<term>Mutation</term>
<term>Paraplégie spasmodique héréditaire de Strümpell-Lorrain</term>
<term>Pathologie du système nerveux</term>
<term>Substance blanche</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term>
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<front><div type="abstract" xml:lang="en">Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult‐onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss‐of‐function of the paraplegin‐AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7‐HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP. © 2010 Movement Disorder Society</div>
</front>
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<affiliations><list><country><li>Allemagne</li>
</country>
<region><li>District de Münster</li>
<li>Rhénanie-du-Nord-Westphalie</li>
</region>
<settlement><li>Münster</li>
</settlement>
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<tree><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Warnecke, Tobias" sort="Warnecke, Tobias" uniqKey="Warnecke T" first="Tobias" last="Warnecke">Tobias Warnecke</name>
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<name sortKey="Deppe, Michael" sort="Deppe, Michael" uniqKey="Deppe M" first="Michael" last="Deppe">Michael Deppe</name>
<name sortKey="Duning, Thomas" sort="Duning, Thomas" uniqKey="Duning T" first="Thomas" last="Duning">Thomas Duning</name>
<name sortKey="Dziewas, Rainer" sort="Dziewas, Rainer" uniqKey="Dziewas R" first="Rainer" last="Dziewas">Rainer Dziewas</name>
<name sortKey="Lohmann, Hubertus" sort="Lohmann, Hubertus" uniqKey="Lohmann H" first="Hubertus" last="Lohmann">Hubertus Lohmann</name>
<name sortKey="Mohammadi, Siawoosh" sort="Mohammadi, Siawoosh" uniqKey="Mohammadi S" first="Siawoosh" last="Mohammadi">Siawoosh Mohammadi</name>
<name sortKey="Ringelstein, E Bernd" sort="Ringelstein, E Bernd" uniqKey="Ringelstein E" first="E. Bernd" last="Ringelstein">E. Bernd Ringelstein</name>
<name sortKey="Schirmacher, Anja" sort="Schirmacher, Anja" uniqKey="Schirmacher A" first="Anja" last="Schirmacher">Anja Schirmacher</name>
<name sortKey="Schwindt, Wolfram" sort="Schwindt, Wolfram" uniqKey="Schwindt W" first="Wolfram" last="Schwindt">Wolfram Schwindt</name>
<name sortKey="Young, Peter" sort="Young, Peter" uniqKey="Young P" first="Peter" last="Young">Peter Young</name>
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