Search tips
Search criteria

Results 1-6 (6)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  De novo point mutations in patients diagnosed with ataxic cerebral palsy 
Brain  2015;138(7):1817-1832.
Cerebral palsy is commonly attributed to perinatal asphyxia. However, Schnekenberg et al. describe here four individuals with ataxic cerebral palsy likely due to de novo dominant mutations associated with increased paternal age. Therefore, patients with cerebral palsy should be investigated for genetic causes before the disorder is ascribed to asphyxia.
Cerebral palsy is commonly attributed to perinatal asphyxia. However, Schnekenberg et al. describe here four individuals with ataxic cerebral palsy likely due to de novo dominant mutations associated with increased paternal age. Therefore, patients with cerebral palsy should be investigated for genetic causes before the disorder is ascribed to asphyxia.
Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.
PMCID: PMC4572487  PMID: 25981959
cerebral palsy; ataxia; de novo; intellectual disability
2.  β-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: protein complex critical for sodium channel activity is impaired by SCA5-associated mutations 
Human Molecular Genetics  2014;23(14):3875-3882.
Beta III spectrin is present throughout the elaborate dendritic tree of cerebellar Purkinje cells and is required for normal neuronal morphology and cell survival. Spinocerebellar ataxia type 5 (SCA5) and spectrin associated autosomal recessive cerebellar ataxia type 1 are human neurodegenerative diseases involving progressive gait ataxia and cerebellar atrophy. Both disorders appear to result from loss of β-III spectrin function. Further elucidation of β-III spectrin function is therefore needed to understand disease mechanisms and identify potential therapeutic options. Here, we report that β-III spectrin is essential for the recruitment and maintenance of ankyrin R at the plasma membrane of Purkinje cell dendrites. Two SCA5-associated mutations of β-III spectrin both reduce ankyrin R levels at the cell membrane. Moreover, a wild-type β-III spectrin/ankyrin-R complex increases sodium channel levels and activity in cell culture, whereas mutant β-III spectrin complexes fail to enhance sodium currents. This suggests impaired ability to form stable complexes between the adaptor protein ankyrin R and its interacting partners in the Purkinje cell dendritic tree is a key mechanism by which mutant forms of β-III spectrin cause ataxia, initially by Purkinje cell dysfunction and exacerbated by subsequent cell death.
PMCID: PMC4065159  PMID: 24603075
3.  β-III spectrin is critical for development of Purkinje cell dendritic tree and spine morphogenesis 
The Journal of Neuroscience  2011;31(46):16581-16590.
Mutations in the gene encoding β-III spectrin give rise to spinocerebellar ataxia type 5 (SCA5), a neurodegenerative disease characterized by progressive thinning of the molecular layer, loss of Purkinje cells and increasing motor deficits. A mouse lacking full-length β-III spectrin (β-III−/−) displays a similar phenotype. In vitro and in vivo analyses of Purkinje cells lacking β-III spectrin, reveal a critical role for β-III spectrin in Purkinje cell morphological development. Disruption of the normally well-ordered dendritic arborization occurs in Purkinje cells from β-III−/− mice, specifically showing a loss of monoplanar organization, smaller average dendritic diameter and reduced densities of Purkinje cell spines and synapses. Early morphological defects appear to affect distribution of dendritic, but not axonal, proteins. This study confirms that thinning of the molecular layer associated with disease pathogenesis is a consequence of Purkinje cell dendritic degeneration, as Purkinje cells from 8-month old β-III−/− mice have drastically reduced dendritic volumes, surface areas and total dendritic lengths compared to 5–6 week old β-III−/− mice. These findings highlight a critical role of β-III spectrin in dendritic biology and are consistent with an early developmental defect in β-III−/− mice, with abnormal Purkinje cell dendritic morphology potentially underlying disease pathogenesis.
PMCID: PMC3374928  PMID: 22090485
4.  β-III spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes with binding to Arp1 and protein trafficking from the Golgi 
Human Molecular Genetics  2010;19(18):3634-3641.
Spinocerebellar ataxia type 5 (SCA5) is an autosomal dominant neurodegenerative disorder caused by mutations in β-III spectrin. A mouse lacking full-length β-III spectrin has a phenotype closely mirroring symptoms of SCA5 patients. Here we report the analysis of heterozygous animals, which show no signs of ataxia or cerebellar degeneration up to 2 years of age. This argues against haploinsufficiency as a disease mechanism and points towards human mutations having a dominant-negative effect on wild-type (WT) β-III spectrin function. Cell culture studies using β-III spectrin with a mutation associated with SCA5 (L253P) reveal that mutant protein, instead of being found at the cell membrane, appears trapped in the cytoplasm associated with the Golgi apparatus. Furthermore, L253P β-III spectrin prevents correct localization of WT β-III spectrin and prevents EAAT4, a protein known to interact with β-III spectrin, from reaching the plasma membrane. Interaction of β-III spectrin with Arp1, a subunit of the dynactin–dynein complex, is also lost with the L253P substitution. Despite intracellular accumulation of proteins, this cellular stress does not induce the unfolded protein response, implying the importance of membrane protein loss in disease pathogenesis. Incubation at lower temperature (25°C) rescues L253P β-III spectrin interaction with Arp1 and normal protein trafficking to the membrane. These data provide evidence for a dominant-negative effect of an SCA5 mutation and show for the first time that trafficking of both β-III spectrin and EAAT4 from the Golgi is disrupted through failure of the L253P mutation to interact with Arp1.
PMCID: PMC2928133  PMID: 20603325
5.  Loss of β-III spectrin leads to Purkinje cell dysfunction recapitulating the behaviour and neuropathology of SCA5 in humans 
Mutations in SPTBN2, the gene encoding β-III spectrin, cause spinocerebellar ataxia type 5 in humans (SCA5), a neurodegenerative disorder resulting in loss of motor coordination. How these mutations give rise to progressive ataxia and what the precise role β-III spectrin plays in normal cerebellar physiology are unknown. We developed a mouse lacking full length β-III spectrin and found that homozygous mice reproduced features of SCA5 including gait abnormalities, tremor, deteriorating motor coordination, Purkinje cell loss and cerebellar atrophy (molecular layer thinning). In vivo analysis reveals an age-related reduction in simple spike firing rate in surviving β-III−/− Purkinje cells while in vitro studies show these neurons to have reduced spontaneous firing, smaller sodium currents and dysregulation of glutamatergic neurotransmission. Our data suggest an early loss of EAAT4- (protein interactor of β-III spectrin) and subsequent loss of GLAST-mediated uptake may play a role in neuronal pathology. These findings implicate a loss of β-III spectrin function in SCA5 pathogenesis and indicate there are at least two physiological effects of β-III spectrin loss that underpin a progressive loss of inhibitory cerebellar output, namely an intrinsic Purkinje cell membrane defect due to reduced sodium currents and alterations in glutamate signaling.
PMCID: PMC2857506  PMID: 20371805
ataxia; cerebellum; motor coordination; glutamate transporters; excitotoxicity; neurodegeneration
6.  Control of synaptic vesicle endocytosis by an extracellular signalling molecule 
Nature Communications  2013;4:2394.
Signalling cascades control multiple aspects of presynaptic function. Synaptic vesicle endocytosis was assumed to be exempt from modulation, due to its essential role maintaining synaptic vesicle supply and thus neurotransmission. Here we show that brain-derived neurotrophic factor arrests the rephosphorylation of the endocytosis enzyme dynamin I via an inhibition of glycogen synthase kinase 3. This event results in a selective inhibition of activity-dependent bulk endocytosis during high-intensity firing. Furthermore, the continued presence of brain-derived neurotrophic factor alleviates the rundown of neurotransmission during high activity. Thus, synaptic strength can be modulated by extracellular signalling molecules via a direct inhibition of a synaptic vesicle endocytosis mode.
Synaptic vesicle endocytosis is required for neurotransmission at nerve terminals. Smillie et al. show that brain-derived neurotrophic factor inhibits a specific type of synaptic vesicle endocytosis, which reverses the depression of neurotransmission observed during high-intensity stimulation.
PMCID: PMC3778765  PMID: 23999152

Results 1-6 (6)