Autosomal Dominant Hereditary Spastic Paraplegia Research Articles

Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics

Hereditary spastic paraplegia (HSP) is characterized by progressive weakness and spasticity of the lower limbs, caused by the specific degeneration of the corticospinal tracts, the longest axons in humans. Most cases of the autosomal dominant form of the disease are due to mutations in the SPG4 gene, which encodes spastin, an ATPase belonging to the AAA family. The cellular pathways in which spastin operates and its role in causing degeneration of motor axons are currently unknown. By expressing wild-type or ATPase-defective spastin in several cell types, we now show that spastin interacts dynamically with microtubules. Spastin association with the microtubule cytoskeleton is mediated by the N-terminal region of the protein, and is regulated through the ATPase activity of the AAA domain. Expression of all the missense mutations into the AAA domain, which were previously identified in patients, leads to constitutive binding to microtubules in transfected cells and induces the disappearance of the aster and the formation of thick perinuclear bundles, suggesting a role of spastin in microtubule dynamics. Consistently, wild-type spastin promotes microtubule disassembly in transfected cells. These data suggest that spastin may be involved in microtubule dynamics similarly to the highly homologous microtubule-severing protein, katanin. Impairment of fine regulation of the microtubule cytoskeleton in long axons, due to spastin mutations, may underlie pathogenesis of HSP.

Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.

The hereditary spastic paraplegias (HSPs; Strümpell-Lorrain syndrome, MIM number 18260) are a diverse class of disorders characterized by insidiously progressive lower-extremity spastic weakness (reviewed in refs. 1-3). Eight autosomal dominant HSP (ADHSP) loci have been identified, the most frequent of which is that linked to the SPG4 locus on chromosome 2p22 (found in approximately 42%), followed by that linked to the SPG3A locus on chromosome 14q11-q21 (in approximately 9%). Only SPG4 has been identified as a causative gene in ADHSP. Its protein (spastin) is predicted to participate in the assembly or function of nuclear protein complexes. Here we report the identification of mutations in a newly identified GTPase gene, SPG3A, in ADHSP affected individuals.

SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q

The authors studied two families with autosomal recessive hereditary spastic paraplegia (HSP) complicated by the presence of additional symptoms of pigmented maculopathy, distal amyotrophy, dysarthria, mental retardation, and further intellectual deterioration. Evidence was obtained for linkage to a locus on chromosome 14q that is distinct from the SPG3 locus for autosomal dominant HSP (D14S77: lod score of 4.20 at zero recombination). Haplotype construction of nearby markers confirms the existence of this novel HSP locus (SPG15) and narrows it to a 19-cM interval flanked by D14S1038 and D14S61.

A large Japanese SPG4 family with a novel insertion mutation of the SPG4 gene: a clinical and genetic study

We studied a large Japanese family with autosomal dominant pure hereditary spastic paraplegia (ADPHSP) clinically and genetically. To date, seven loci causing ADPHSP have been mapped to chromosomes 14q, 2p, 15q, 8q, 12q, 2q, and 19q. Among these loci, the SPG4 locus on chromosome 2p21–p22 has been shown to account for approximately 40% of all autosomal dominant hereditary spastic paraplegia (ADHSP) families. Very recently, Hazan et al. identified the SPG4 gene encoding a new member of the AAA (ATPases associated with diverse cellular activities) protein family, named spastin. We found a novel insertion mutation (nt1272–1273insA) in exon 8 of the SPG4 gene in the present family. Our study is the first to confirm the causative mutation of the SPG4 gene in Japanese. Clinically, it is noteworthy that the disease progression in the patients of this family was slow in spite of the late onset, and more than half of the patients showed severe constipation in addition to pure spastic paraplegia.

Silver syndrome is not linked to any of the previously established autosomal dominant hereditary spastic paraplegia loci.

The hereditary spastic paraplegias are a clinically variable and genetically heterogeneous group of disorders characterized by progressive and lower limb spasticity and weakness. Silver syndrome (SS) is a particularly disabling autosomal dominant form of the disease in which there is associated wasting of the hand muscles. In view of the fact that genes for hereditary spastic paraplegia can produce highly variable phenotypes, the eight known autosomal dominant loci were investigated for linkage to Silver syndrome. Genotyping of these loci in two large multigenerational families was incompatible with linkage to any of these regions, suggesting that an additional locus is responsible for this syndrome.

Prenatal diagnosis of hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a degenerative neurologic disorder that causes progressive, often severe, spastic weakness in the legs. Autosomal dominant HSP is a highly penetrant, genetically heterogeneous disorder with loci present on chromosomes 2p21-24, 2q24-34, 8q23-24, 10q23.3-24, 12q13, 14q12-23, 15q11-14 and 19q13.1. We identified a large HSP kindred in which the disorder was tightly linked to chromosome 14q12-23. We tested chorionic villus DNA samples of two at-risk fetuses for inheritance of microsatellite polymorphisms flanking and within this locus that segregated with the disease in this family. Whereas samples from the first fetus showed inheritance of a haplotype segregating with the disease allele (indicating high risk of developing HSP), samples from the second fetus showed inheritance of a haplotype segregating with the normal allele (indicating low risk of developing HSP). This is the first report of prenatal testing for HSP. Published in 2001 by John Wiley & Sons, Ltd.

Mitochondrial analysis in autosomal dominant hereditary spastic paraplegia.

The hereditary spastic paraplegias (HSP) are a group of genetically heterogeneous disorders in which the predominant symptom is insidiously progressive, bilaterally symmetric, lower extremity spastic weakness. To date, five autosomal dominant forms, three autosomal recessive forms, and two X-linked forms of HSP have been defined.1 Autosomal recessive HSP linked to chromosome 16 is due to paraplegin gene mutation.2 Several autosomal recessive HSP subjects with paraplegin gene mutations were shown to have ragged red fibers and cytochrome c oxidase (COX)–deficient fibers consistent with mitochondrial disturbance.2 Previously, we reported that a muscle biopsy from a subject with autosomal dominant HSP linked to chromosome 8q had no evidence of mitochondrial abnormalities.3 We undertook the current investigation to determine whether mitochondrial abnormalities were common features in other types of autosomal dominant HSP linked to chromosomes 2p, 14q, and 15q. We identified HSP kindreds in which two-point lod scores to the chromosome 2p, 14q, or 15q exceeded 3.0. The HSP kindred linked to chromosome …

Novel mutations in spastin gene and absence of correlation with age at onset of symptoms

Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five loci identified by linkage analysis. Recently, mutations in spastin were identified in SPG4, the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22. We identified five novel mutations in the spastin gene in five families with SPG4 mutations from North America and Tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms.

Hereditary spastic paraplegia caused by mutations in the SPG4 gene.

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs. The SPG4 locus at 2p21-p22 accounts for 40-50% of all AD-HSP families. The SPG4 gene was recently identified. It is ubiquitously expressed in adult and foetal tissues and encodes spastin, an ATPase of the AAA family. We have now identified four novel SPG4 mutations in German AD-HSP families, including one large family for which anticipation had been proposed. Mutations include one frame-shift and one missense mutation, both affecting the Walker motif B. Two further mutations affect two donor splice sites in introns 12 and 16, respectively. RT-PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA. All mutations are predicted to cause loss of functional protein. In conclusion, we confirm in German families that SPG4 mutations cause AD-HSP. Our data suggest that SPG4 mutations exert their dominant effect not by gain of function but by haploinsufficiency. If a threshold level of spastin were critical for axonal preservation, such threshold dosage effects might explain the variable expressivity and incomplete penetrance of SPG4-linked AD-HSP.

Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: analysis of muscle beta 1 syntrophin.

The autosomal dominant hereditary spastic paraplegias (AD-HSP) are a heterogeneous group of degenerative disorders of the central motor system, characterized by progressive spasticity of the lower limbs. Five loci for pure AD-HSP have been identified to date: SPG3 at 14q, SPG4 at 2p, SPG6 at 15q, SPG8 at 8q, and more recently SPG10 at 12q. We have analyzed a Brazilian family with 16 affected individuals by pure AD-HSP who developed progressive gait disturbance with onset at age 18-26 years. Linkage analysis performed with 13 relatives (6 affected and 7 normal) excluded SPG3, SPG4, and SPG6 as candidate regions. However, positive LOD scores were obtained with markers flanking the candidate region for the SPG8 locus [maximum two point Lod score (Zmax) = 3.3 at theta = 0 for D8S1804]. In this region lies the syntrophin beta 1 gene (SNT2B1), a widely expressed dystrophin-associated protein and therefore a good positional and functional candidate for this disease. Immunohistochemical and Western Blot (WB) studies showed that the distribution, expression, and apparent molecular weight of the beta 1 syntrophin protein were comparable to those of normal control individuals. Therefore, it is unlikely that defects in this protein are related to SPG8, at least in the present family.

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro- gressive spasticity of the lower limbs. Five AD-HSP loci have been mapped to chromosomes 14q, 2p, 15q, 8q and 12q. The SPG4 locus at 2p21-p22 has been shown to account for approximately 40% of all AD-HSP families. SPG4 encoding spastin, a putative nuclear AAA protein, has recently been identified. Here, sequence analysis of the 17 exons of SPG4 in 87 unrelated AD-HSP patients has resulted in the detection of 34 novel mutations. These SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense (28%), nonsense (15%) and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers (14/238) and patients unaware of symptoms (45/238), and permitted the redefinition of this frequent form of AD-HSP.

A New Locus for Autosomal Dominant Pure Spastic Paraplegia, on Chromosome 2q24-q34

Hereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous disorders causing progressive spasticity and weakness of the lower limbs. We report a large family of French descent with autosomal dominant pure HSP. We excluded genetic linkage to the known loci causing HSP and performed a genomewide search. We found evidence for linkage of the disorder to polymorphic markers on chromosome 2q24-q34: a maximum LOD score of 3. 03 was obtained for marker D2S2318. By comparison with families having linkage to the major locus of pure autosomal dominant HSP (SPG4 on chromosome 2p), there were significantly more patients without Babinski signs, with increased reflexes in the upper limbs, and with severe functional handicaps.

A Locus for Autosomal Dominant “Pure” Hereditary Spastic Paraplegia Maps to Chromosome 19q13

Genetic loci for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) have been mapped to chromosomes 2p, 8q, 12q, 14q, and 15q. We undertook a genomewide linkage screen of a large family with ADPHSP, for which linkage at all previously identified ADPHSP loci was excluded. Analysis of markers on chromosome 19q gave a peak pairwise LOD score of 3.72 at D19S420, allowing assignment of a novel ADPHSP locus (which we have termed "SPG12") to this region. Haplotype construction and analysis of recombination events narrowed the SPG12 locus to a 16.1-cM region between markers D19S868 and D19S902.

Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia.

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes.

Autosomal dominant spastic paraplegia

To map the gene responsible for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) in a large affected family. Autosomal dominant pure hereditary spastic paraplegia (ADPHSP) is genetically heterogeneous, and loci have been mapped at chromosomes 2p (SPG4), 14q (SPG3), 15q (SPG6), and recently, in a single family, at chromosome 8q24 (SPG8). The authors carried out a genomewide linkage screen on a large family with ADPHSP, for which linkage to the chromosome 2, 14, and 15 loci was excluded. Analysis of markers on chromosome 8q24 gave a peak two-point lod score of 4.49 at marker D8S1799. Analysis of recombination events in this family and in the previously published SPG8-linked family narrowed the SPG8 locus from 6.2 cM to a 3.4-cM region between markers D8S1804 and D8S1179. In another four families, linkage to all four known ADPHSP loci was excluded. The SPG8-linked family had a significantly older mean age at onset of symptoms and had significantly more wheelchair-using patients than the four linkage-excluded families. These results contain the presence of an autosomal dominant pure hereditary spastic paraplegia (ADPHSP) locus at chromosome 8q24 and strongly suggest that there are at least five ADPHSP loci. The data provide additional evidence for locus-phenotype correlations in ADPHSP.

A Fine Integrated Map of the SPG4 Locus Excludes an Expanded CAG Repeat in Chromosome 2p-Linked Autosomal Dominant Spastic Paraplegia

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous disorder characterized by progressive spasticity of the lower limbs. A major locus (SPG4) causing AD-HSP in about 40% of the families was mapped to chromosome 2p. The analysis of six SPG4-linked AD-HSP families using the RED procedure previously showed the expansion of a CAG repeat in affected individuals. To identify the gene responsible for this form of HSP, we have constructed a 3.5-Mb YAC contig flanked by loci D2S400 and D2S367, have subcloned five of these YACs spanning the candidate region into cosmids, and screened these cosmid libraries for the presence of CAG repeat sequences. Four CAG repeats have been identified but none of them is expanded in 26 patients from 13 SPG4-linked AD-HSP families. A gene map comprising 21 transcripts was established using expressed sequence tags (ESTs) assigned previously to this region of 2p21–p22 with radiation hybrid panels GeneBridge 4 and G3. Full-length cDNAs corresponding to the 14 ESTs mapping to the SPG4 interval flanked by loci D2S352 and D2S2347 were isolated and sequenced. None contains a CAG repeat in its coding sequence. Finally, we have assembled a BAC contig composed of 37 clones that were also screened for the presence of CAG repeats; this failed to detect additional repeats to those identified on YACs.

Locus-phenotype correlations in autosomal dominant pure hereditary spastic paraplegia. A clinical and molecular genetic study of 28 United Kingdom families.

This study aimed to describe the clinical phenotype of a large collection of families with autosomal dominant pure hereditary spastic paraplegia (ADPHSP), to examine the relative frequency of each of the three known ADPHSP genes within this population, to assess locus-phenotype correlation in ADPHSP and to ascertain whether there are clinical subgroups within genetically defined populations of ADPHSP families. We examined 306 family members, 144 affected, from 28 families with ADPHSP. Linkage analysis at the three known ADPHSP loci allowed us to categorize the families into three groups: (i) those families showing linkage to the chromosome 2 ADPHSP locus (seven families); (ii) those in which linkage to all known loci was excluded (five families); and (iii) those in which linkage results were inconclusive. There was a correlation between linkage group and clinical features, with chromosome 2-linked families having a later age at onset of symptoms (P = 0.001) and later age before commencing walking stick use (P = 0.007) than those families in which linkage to all known ADPHSP loci was excluded. There were no clinical differences between the families showing linkage to the chromosome 2 locus, but there were clinical differences between the families in which linkage to all of the known loci had been excluded (P < 0.0001). We conclude that the chromosome 2 ADPHSP gene is a frequent cause of ADPHSP in UK families, that the responsible gene has not yet been mapped in a significant proportion of families and that certain clinical features of ADPHSP, including age at onset, are at least in part determined by genetic locus.

A New Locus for Autosomal Dominant “Pure” Hereditary Spastic Paraplegia Mapping to Chromosome 12q13, and Evidence for Further Genetic Heterogeneity

Autosomal dominant pure hereditary spastic paraplegia (ADPHSP) is clinically characterized by slowly progressive lower-limb spasticity. The condition is genetically heterogeneous, and loci have been mapped at chromosomes 2p, 8q, 14q, and 15q. We have performed a genomewide linkage screen on a large family with ADPHSP, in which linkage to all four previously known loci was excluded. Analysis of markers on chromosome 12q gave a peak pairwise LOD score of 3.61 at D12S1691, allowing us to assign a new locus for ADPHSP (a locus that we have designated "SPG10") to this region. Haplotype construction and analysis of recombination events narrowed the SPG10 locus to a 9.2-cM region between markers D12S368 and D12S83. In addition, our data strongly suggest that there are at least six ADPHSP loci, since we describe a further family in which linkage to all five known ADPHSP loci has been excluded.

Clinical heterogeneity of autosomal recessive spastic paraplegias: analysis of 106 patients in 46 families.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive and predominant spasticity of the lower limbs, in which dominant, recessive, and X-linked forms have been described. While autosomal dominant HSP has been extensively studied, autosomal recessive HSP is less well known and is considered a rare condition. To analyze the clinical presentation in a large group of patients with autosomal recessive HSP from Portugal and Algeria to define homogeneous groups that could serve as a guide for future molecular studies. Clinical features in 106 patients belonging to 46 Portuguese and Algerian families with autosomal recessive HSP are presented, as well as the results of molecular studies in 23 of these families. Five phenotypes are defined: (1) pure early-onset families, (2) pure lateonset families, (3) complex families with mental retardation, (4) complex families with mental retardation and peripheral neuropathy, and (5) complex families with cerebellar ataxia. Six additional families have specific complex presentations, each of which is unique in the present series. Pyramidal signs in the upper limbs and pes cavus are frequent findings, while pseudobulbar signs, including dysarthria, dysphagia, and brisk jaw jerks, are more frequent in the complex forms. The complex forms have a poorer prognosis, while pure forms, particularly those with early onset, are more benign. One Algerian pure early-onset kindred was linked to the locus on chromosome 8, previously reported in 4 Tunisian families. Two of the Portuguese kindreds with complex forms (one with mental retardation and the other associated with hypoplasia of the corpus callosum) showed linkage to the locus recently identified on chromosome 16. Although autosomal recessive HSP represents a heterogeneous group of diseases, some phenotypes can be defined by analyzing a large group of patients. The fact that only one Algerian family was linked to chromosome 8 suggests that this is a rare localization even in kindreds with the same ethnic background. Linkage to chromosome 16 was found in 2 clinically diverse Portuguese kindreds, illustrating that this locus is also rare and may correspond to different phenotypes.

Phenotypic analysis of autosomal dominant hereditary spastic paraplegia linked to chromosome 8q

To describe clinical, electrophysiologic, neuroimaging, and muscle biopsy features in a hereditary spastic paraplegia (HSP) kindred linked to a new HSP locus on chromosome 8q. HSP is a genetically diverse group of disorders characterized by insidiously progressive spastic weakness in the legs. We recently analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage to a novel HSP locus on chromosome 8q23-24. Clinical analysis, nerve conduction studies, electromyography, somatosensory evoked potentials, MRI of brain and spinal cord, and muscle biopsy for mitochondrial analysis were performed in members of the first HSP kindred linked to chromosome 8q. Fifteen individuals showed insidiously progressive spastic paraparesis beginning between ages 22 and 60 years (average, 37.2 years). Spinal cord MRI in 1 moderately affected subject showed significant atrophy of the thoracic spinal cord as determined by cross-sectional area measurements. Somatosensory evoked potential recording, electromyography, nerve conduction studies, and muscle biopsy, including histochemical and biochemical analysis of mitochondrial function, were normal. The phenotype in this family is that of typical, but severe, uncomplicated HSP. Other than apparently increased severity, there were no clinical features that distinguished this family from autosomal dominant HSP linked to loci on chromosomes 2p, 14q, and 15q. This clinical similarity between different genetic types of autosomal dominant HSP raises the possibility that genes responsible for these clinically indistinguishable disorders may participate in a common biochemical cascade. Normal results of muscle histochemical and biochemical analysis suggest that mitochondrial disturbance, a feature of chromosome 16-linked autosomal recessive HSP due to paraplegin gene mutations, is not a feature of chromosome 8q-linked autosomal dominant HSP and may not be a common factor of HSP in general.