A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects
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A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects. / Warnecke, Tobias; Duning, Thomas; Schirmacher, Anja; Mohammadi, Siawoosh; Schwindt, Wolfram; Lohmann, Hubertus; Dziewas, Rainer; Deppe, Michael; Ringelstein, E Bernd; Young, Peter.
In: MOVEMENT DISORD, Vol. 25, No. 4, 15.03.2010, p. 413-20.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects
AU - Warnecke, Tobias
AU - Duning, Thomas
AU - Schirmacher, Anja
AU - Mohammadi, Siawoosh
AU - Schwindt, Wolfram
AU - Lohmann, Hubertus
AU - Dziewas, Rainer
AU - Deppe, Michael
AU - Ringelstein, E Bernd
AU - Young, Peter
PY - 2010/3/15
Y1 - 2010/3/15
N2 - 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.
AB - 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.
KW - Adult
KW - Amino Acid Substitution
KW - Atrophy
KW - Brain
KW - DNA Mutational Analysis
KW - DNA, Recombinant
KW - Diffusion Magnetic Resonance Imaging
KW - Electrodiagnosis
KW - Female
KW - Genetic Predisposition to Disease
KW - Genetic Testing
KW - Genotype
KW - Humans
KW - Metalloendopeptidases
KW - Middle Aged
KW - Muscle Fibers, Skeletal
KW - Neural Pathways
KW - Neuropsychological Tests
KW - Phenotype
KW - Point Mutation
KW - Spastic Paraplegia, Hereditary
KW - Twins, Dizygotic
KW - Twins, Monozygotic
U2 - 10.1002/mds.22949
DO - 10.1002/mds.22949
M3 - SCORING: Journal article
C2 - 20108356
VL - 25
SP - 413
EP - 420
JO - MOVEMENT DISORD
JF - MOVEMENT DISORD
SN - 0885-3185
IS - 4
ER -