A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation

Ruhr-Universität Bochum, Bochum, North Rhine-Westphalia, Germany
Neurology (Impact Factor: 8.29). 08/2007; 69(4):368-75. DOI: 10.1212/01.wnl.0000266667.91074.fe
Source: PubMed


Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by progressive spastic paraparesis of the lower limbs.
To identify the genotype and characterize the phenotype in a family with a novel form of complicated autosomal recessive hereditary spastic paraparesis (ARHSP).
Six subjects of a Turkish family were examined by clinical evaluation, detailed neuropsychological testing, neurophysiologic studies, MRI, diffusion tensor imaging (DTI), and mutation analysis of SPG7 gene.
Three individuals were affected by a juvenile-onset form of complicated ARHSP due to the missense mutation c.2075G>C in exon 15 of the SPG7 gene in the homozygous state, substituting serine with threonine at codon 692. As additional clinical features, cerebellar syndrome, supranuclear palsy, and cognitive impairment, particularly disturbance of attention and executive functions, were found. MRI showed cerebellar atrophy and mild frontal cerebral atrophy. DTI revealed bilateral disturbance of white matter integrity in corticospinal tracts, frontal lobes, and the midbrain.
The new SPG7 gene mutation leads to a novel complicated autosomal recessive hereditary spastic paraparesis phenotype that widens the spectrum of different brain systems that are optionally affected in hereditary spastic paraplegia (HSP). In this novel phenotype, spastic paraparesis is related to cerebral damage of corticospinal tracts. Impairment of attention and executive functions is due to white matter loss in frontal lobes. Furthermore, supranuclear palsy is caused by white matter damage in the midbrain. This multisystem affection, which was detected by the use of diffusion tensor imaging, may reflect a mitochondrial dysfunction that contributes to the underlying pathogenesis of SPG7-HSP.

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    • "Hereditary spastic paraplegias (HSP) are a group of heterogeneous neurodegenerative disorders, which are clinically characterized by progressive spastic paralysis in the lower limbs [Depienne et al., 2007; Harding, 1983]. Mutations in the SPG7 gene (MIM 602783) cause an autosomal recessive (AR) form of HSP [Arnoldi et al., 2008; Brugman et al., 2008; Casari et al., 1998; Elleuch et al., 2006; McDermott et al., 2001; Tzoulis et al., 2008; Warnecke et al., 2007; Wilkinson et al., 2004]. The SPG7 gene codes for paraplegin, which contains an M41 metallopeptidase domain and an ATPase domain characteristic of the AAA family of ATPases [Langer, 2000]. "
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    ABSTRACT: An autosomal recessive form of hereditary spastic paraplegia (AR-HSP) is primarily caused by mutations in the SPG7 gene, which codes for paraplegin, a subunit of the hetero-oligomeric m-AAA protease in mitochondria. In the current study, sequencing of the SPG7 gene in the genomic DNA of 25 unrelated HSP individuals/families led to the identification of two HSP patients with compound heterozygous mutations (p.G349S/p.W583C and p.A510V/p.N739KfsX741) in the coding sequence of the SPG7 gene. We used a yeast complementation assay to evaluate the functional consequence of novel SPG7 sequence variants detected in the HSP patients. We assessed the proteolytic activity of hetero-oligomeric m-AAA proteases composed of paraplegin variant(s) and proteolytically inactive forms of AFG3L2 (AFG3L2(E575Q) or AFG3L2(K354A)) upon expression in m-AAA protease-deficient yeast cells. We demonstrate that the newly identified paraplegin variants perturb the proteolytic function of hetero-oligomeric m-AAA protease. Moreover, commonly occurring silent polymorphisms such as p.T503A and p.R688Q could be distinguished from mutations (p.G349S, p.W583C, p.A510V, and p.N739KfsX741) in our HSP cohort. The yeast complementation assay thus can serve as a reliable system to distinguish a pathogenic mutation from a silent polymorphism for any novel SPG7 sequence variant, which will facilitate the interpretation of genetic data for SPG7.
    Human Mutation 05/2010; 31(5):617-21. DOI:10.1002/humu.21226 · 5.14 Impact Factor
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    • "chromosomal region, is responsible for a recessive form of the disease with both pure and complex phenotypes [Casari et al., 1998]. Only 16 mutations and several heterozygous amino acid changes, including both polymorphisms and rare variants with unknown effects, were reported in the SPG7 gene (MIM] 602783) [Casari et al., 1998; McDermott et al., 2001; Wilkinson et al., 2004; Elleuch et al., 2006; Warnecke et al., 2007]. A heterozygous SPG7 microdeletion segregating in an HSP family with dominant inheritance was also reported [McDermott et al., 2001]. "
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    ABSTRACT: Mutations in the SPG7 gene encoding a mitochondrial protein termed paraplegin, are responsible for a recessive form of hereditary spastic paraparesis. Only few studies have so far been performed in large groups of hereditary spastic paraplegia (HSP) patients to determine the frequency of SPG7 mutations. Here, we report the result of a mutation screening conducted in a large cohort of 135 Italian HSP patients with the identification of six novel point mutations and one large intragenic deletion. Sequence analysis of the deletion breakpoint, together with secondary structure predictions of the deleted region, indicate that a complex rearrangement, likely caused by extensive secondary structure formation mediated by the short interspersed nuclear element (SINE) retrotransposons, is responsible for the deletion event. Biochemical studies performed on fibroblasts from three mutant patients revealed mild and heterogeneous mitochondrial dysfunctions that would exclude a specific association of a complex I defect with the pathology at the fibroblast level. Overall, our data confirm that SPG7 point mutations are rare causes of HSP, in both sporadic and familial forms, while underlying the puzzling and intriguing aspects of histological and biochemical consequences of paraplegin loss.
    Human Mutation 04/2008; 29(4):522-31. DOI:10.1002/humu.20682 · 5.14 Impact Factor
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