SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia.
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ABSTRACT: Background
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common form of complex hereditary spastic paraplegia. The genetic lesion underlying ARHSP-TCC was localized to chromosome 15q13-q15 and given the designation SPG11. Recently, the gene encoding spatacsin (KIAA1840) has been shown to contain mutations that underlie the majority of ARHSP-TCC cases.Methods
We present a complete analysis of the 40 coding exons of this gene in patients with sporadic (n = 25) or familial (20 probands) complex hereditary spastic paraplegia with and without thinning of the corpus callosum.Results
We identified seven mutations, including deletions, insertions, and nonsense mutations, which were all predicted to lead to premature truncation of the protein.Conclusion
We conclude that mutations on KIAA1840 are frequent in complex autosomal recessive hereditary spastic paraplegia but an infrequent cause of sporadic complex hereditary spastic paraplegia.
SUBMITTER: Paisan-Ruiz C
PROVIDER: S-EPMC2730021 | biostudies-literature | 2008 Apr
REPOSITORIES: biostudies-literature
Publications
SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia.
Paisan-Ruiz C C Dogu O O Yilmaz A A Houlden H H Singleton A A
Neurology 20080312 16 Pt 2
<h4>Background</h4>Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common form of complex hereditary spastic paraplegia. The genetic lesion underlying ARHSP-TCC was localized to chromosome 15q13-q15 and given the designation SPG11. Recently, the gene encoding spatacsin (KIAA1840) has been shown to contain mutations that underlie the majority of ARHSP-TCC cases.<h4>Methods</h4>We present a complete analysis of the 40 coding exons of this gene in pati ...[more]
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Project description:Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11-HSP. Neuropathological analysis of SPG11-HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11-HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11-/- mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11-HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11-HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.
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Project description:ObjectiveHereditary spastic paraplegias (HSPs) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified (SPG1-71) to date. SPG15 and SPG11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early-onset parkinsonism.MethodsWe describe two new cases of SPG15 and investigate cellular changes in SPG15 and SPG11 patient-derived fibroblasts, seeking to identify shared pathogenic themes. Cells were evaluated for any abnormalities in cell division, DNA repair, endoplasmic reticulum, endosomes, and lysosomes.ResultsFibroblasts prepared from patients with SPG15 have selective enlargement of LAMP1-positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of LAMP1-positive structures was also observed in cells from multiple SPG11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the SPG15 protein spastizin/ZFYVE26 and the SPG11 protein spatacsin were interdependent.InterpretationEmerging studies implicating these two proteins in interactions with the late endosomal/lysosomal adaptor protein complex AP-5 are consistent with shared abnormalities in lysosomes, supporting a converging mechanism for these two disorders. Recent work with Zfyve26-/- mice revealed a similar phenotype to human SPG15, and cells in these mice had endolysosomal abnormalities. SPG15 and SPG11 are particularly notable among HSPs because they can also present with juvenile parkinsonism, and this lysosomal trafficking or storage defect may be relevant for other forms of parkinsonism associated with lysosomal dysfunction.
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Project description:BackgroundTo analyze the clinical phenotype of hereditary spastic paraplegia (HSP) caused by SPG11 mutations (SPG11-HSP).MethodsAmong the 17 patients with sporadic HSP who performed whole exome sequencing analysis, six were diagnosed with SPG11-HSP. The clinical and radiologic findings and the results of the electrodiagnostic and neuropsychologic tests were reviewed retrospectively.ResultsThe median age at onset was 16.5 years (range, 13-38 years). Progressive spastic paraparesis was a core feature, and the median spastic paraplegia rating scale score was 24/52 (range, 16-31 points). Additional major symptoms were pseudobulbar dysarthria, intellectual disability, bladder dysfunction, and being overweight. Minor symptoms included upper limbs rigidity and sensory axonopathy. The median body mass index was 26.2 kg/m2 (range, 25.2-32.3 kg/m2). The thin corpus callosum (TCC) was predominant at the rostral body or anterior midbody, and the ears of the lynx sign was seen in all. The follow-up MRI showed the worsening of periventricular white matter (PVWM) signal abnormalities with ventricular widening or the extension of the TCC. Motor evoked potentials (MEP) to the lower limbs showed an absent central motor conduction time (CMCT) in all subjects. The upper limb CMCT was initially absent in three subjects, although it became abnormal in all at the follow-up. The mini-mental state examination median score was 27/30 (range, 26-28) with selective impairment of the attention/calculation domain. The median score of the full-scale intelligence quotient was 48 (range, 42-72) on the Wechsler Adult Intelligence Scale test.ConclusionAttention/calculation deficits and being overweight as well as pseudobulbar dysarthria were common additional symptoms in patients with SPG11-HSP. The rostral body and anterior midbody of the corpus callosum were preferentially thinned, especially in the early stage of the disease. The TCC, PVWM signal changes, and MEP abnormality worsened as the disease progressed.
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Project description:Hereditary spastic paraplegia (HSP) represents a large group of neurological disorders characterized by progressive spasticity of the lower limbs. One subtype of HSP shows an autosomal recessive form of inheritance with thin corpus callosum (ARHSP-TCC), and displays genetic heterogeneity with four known loci. We identified a consanguineous Egyptian family with five affected individuals with ARHSP-TCC. We found linkage to the SPG11 locus and identified a novel homozygous p.Q498X stop codon mutation in exon 7 in the SPG11 gene encoding Spatacsin. Cognitive impairment and polyneuropathy, reported as frequent in SPG11, were not evident. This family supports the importance of SPG11 as a frequent cause for ARHSP-TCC, and expands the clinical SPG11 spectrum.
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Project description:ZFYVE26/Spastizin and SPG11/Spatacsin encode 2 large proteins that are mutated in hereditary autosomal-recessive spastic paraplegia/paraparesis (HSP) type 15 (AR-SPG15) and type 11 (AR-SPG11), respectively. We previously have reported that AR-SPG15-related ZFYVE26 mutations lead to autophagy defects with accumulation of immature autophagosomes. ZFYVE26 and SPG11 were found to be part of a complex including the AP5 (adaptor related protein complex 5) and to have a critical role in autophagic lysosomal reformation with identification of autophagic and lysosomal defects in cells with both AR-SPG15- and AR-SPG11-related mutations. In spite of these similarities between the 2 proteins, here we report that ZFYVE26 and SPG11 are differently involved in autophagy and endocytosis. We found that both ZFYVE26 and SPG11 interact with RAB5A and RAB11, 2 proteins regulating endosome trafficking and maturation, but only ZFYVE26 mutations affected RAB protein interactions and activation. ZFYVE26 mutations lead to defects in the fusion between autophagosomes and endosomes, while SPG11 mutations do not affect this step and lead to a milder autophagy defect. We thus demonstrate that ZFYVE26 and SPG11 affect the same cellular physiological processes, albeit at different levels: both proteins have a role in autophagic lysosome reformation, but only ZFYVE26 acts at the intersection between endocytosis and autophagy, thus representing a key player in these 2 processes. Indeed expression of the constitutively active form of RAB5A in cells with AR-SPG15-related mutations partially rescues the autophagy defect. Finally the model we propose demonstrates that autophagy and the endolysosomal pathway are central processes in the pathogenesis of these complicated forms of hereditary spastic paraparesis. Abbreviations: ALR, autophagic lysosome reformation; AP5, adaptor related protein complex 5; AR, autosomal-recessive; HSP, hereditary spastic paraplegia/paraparesis; ATG14, autophagy related 14; BafA, bafilomycin A1; BECN1, beclin 1; EBSS, Earle balanced salt solution; EEA1, early endosome antigen 1; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; GDP, guanosine diphosphate; GFP, green fluorescent protein; GTP, guanosine triphosphate; HSP, hereditary spastic paraplegias; LBPA, lysobisphosphatidic acid; MAP1LC3B/LC3B, microtubule associated protein 1 light chain 3 beta; MVBs, multivesicular bodies; PIK3C3, phosphatidylinositol 3-kinase, catalytic subunit type 3; PIK3R4, phosphoinositide-3-kinase regulatory subunit 4; PtdIns3P, phosphatidylinositol-3-phosphate; RFP, red fluorescent protein; RUBCN, RUN and cysteine rich domain containing beclin 1 interacting protein; shRNA, short hairpin RNA; SQSTM1/p62, sequestosome 1; TCC: thin corpus callosum; TF, transferrin; UVRAG, UV radiation resistance associated.
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Project description:Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.
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