A novel mutation in PLP1 causes severe hereditary spastic paraplegia type 2

Abstract Background: Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Methods: Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.Results: Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and the this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.Conclusion: In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

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Case report on novel mutation in SPAST gene in Polish family with spastic paraplegia

BMC Neurology ◽

10.1186/s12883-019-1561-6 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Aleksandra Klimkowicz-Mrowiec ◽

Anna Dziubek ◽

Malgorzata Sado ◽

Marek Karpiński ◽

Agnieszka Gorzkowska

Keyword(s):

Case Report ◽

Genetic Testing ◽

Family History ◽

Lower Limb ◽

Hereditary Spastic Paraplegia ◽

Novel Mutation ◽

Family Members ◽

Spastic Paraplegia ◽

Limb Spasticity ◽

Lower Limb Spasticity

Abstract Background Hereditary spastic paraplegia is a large group of degenerative, neurological disorders characterized by progressive lower limb spasticity and weakness. The disease was investigated precisely but still clinicians often make incorrect or late diagnosis. Our aim was to investigate the genetic background and clinical phenotype of spastic paraplegia in large Polish family. Case presentation A 37 years old woman presented with 4-year history of walking difficulties. On neurological examination, she had signs of upper motor lesion in lower extremities. She denied sphincter dysfunction and her cognition was normal. Her family history was positive for individuals with gait problems. The initial diagnosis was familial spastic paraplegia. Genetic testing identified a novel mutation in SPAST gene. All available family members were examined and had genetic testing. The same mutation in SPAST gene was identified in other affected family members. All patients caring the mutation presented with different phenotypes. Conclusion This study presents a family with spastic paraplegia due to a novel mutation c.1390G›T(p.Glu464Term) in SPAST gene. Affected individuals showed a range of phenotypes that varied in their severity. This case report demonstrates, the signs of hereditary spastic paraplegia can be often misdiagnosed with other diseases. Therefore genetic testing should always be considered in patients with lower limb spasticity and positive family history in order to help to establish the correct diagnosis.

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Hereditary spastic paraplegia: a novel mutation and expansion of the phenotype variability in SPG10: Table 1

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2014-308625 ◽

2014 ◽

Vol 86 (6) ◽

pp. 702-704 ◽

Cited By ~ 6

Author(s):

Laura Carosi ◽

Temistocle Lo Giudice ◽

Martina Di Lullo ◽

Federica Lombardi ◽

Carla Babalini ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Novel Mutation ◽

Spastic Paraplegia ◽

Phenotype Variability

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New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP)

Neurogenetics ◽

10.1007/s10048-008-0163-z ◽

2008 ◽

Vol 10 (2) ◽

pp. 105-110 ◽

Cited By ~ 35

Author(s):

Channa Hewamadduma ◽

Christopher McDermott ◽

Janine Kirby ◽

Andrew Grierson ◽

Maria Panayi ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Novel Mutation ◽

Spastic Paraplegia

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Distant homologies and domain conservation of the Hereditary Spastic Paraplegia protein SPG11/ALS5/spatacsin

10.1101/2020.03.08.982389 ◽

2020 ◽

Cited By ~ 1

Author(s):

Alexander L Patto ◽

Cahir J O’Kane

Keyword(s):

Hereditary Spastic Paraplegia ◽

Mass Spectrometry Analysis ◽

Main Function ◽

Spastic Paraplegia ◽

Sm Proteins ◽

Trna Synthetases ◽

Aminoacyl Trna Synthetases ◽

Wide Range ◽

Independent Functions

AbstractLoss-of-function mutations in SPG11 protein (spatacsin) are a common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. To identify regions of the protein that may have functions that are disrupted in disease, we carried out bioinformatic analyses of its conserved regions. An N-terminal region of around 650 amino-acid residues, present in SPG11 across a wide range of metazoan animals, was missing from many insect lineages. Evolutionary loss of this domain correlated with loss of its binding partner, the AP-5 adaptor complex, suggesting that its main function is interaction with AP-5 in intracellular trafficking, and that the remainder of SPG11 carries out AP-5-independent functions. At the C-terminus of SPG11, a spatacsin_C domain showed sequence similarity and predicted structural homology to the Vps16_C domain of the HOPS complex protein Vps16. It localized to acidic compartments, consistent with a role in endolysosomal or autolysosomal transport, like Vps16. Mass spectrometry analysis of binding partners of this domain identified membrane trafficking proteins, some SM proteins, and several aminoacyl-tRNA synthetases. Since mutations affecting SPG11 or aminoacyl-tRNA synthetases can both cause Charcot-Marie-Tooth neuropathy (CMT) type 2, we suggest autolysosomal trafficking as a target process in CMT type 2.

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Novel mutation in the ATL1 with autosomal dominant hereditary spastic paraplegia presented as dysautonomia

Autonomic Neuroscience ◽

10.1016/j.autneu.2014.06.001 ◽

2014 ◽

Vol 185 ◽

pp. 141-143 ◽

Cited By ~ 5

Author(s):

Jung-Won Shin ◽

Keun-Hwa Jung ◽

Soon-Tae Lee ◽

Jangsup Moon ◽

Moon-Woo Seong ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Novel Mutation ◽

Spastic Paraplegia

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RNF170 ‐Related Hereditary Spastic Paraplegia: Confirmation by a Novel Mutation

Movement Disorders ◽

10.1002/mds.28371 ◽

2020 ◽

Author(s):

Jean‐Madeleine de Sainte Agathe ◽

Sandra Mercier ◽

Jean‐Yves Mahé ◽

Yann Péréon ◽

Julien Buratti ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Novel Mutation ◽

Spastic Paraplegia

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Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia

The Journal of Cell Biology ◽

10.1083/jcb.200312012 ◽

2004 ◽

Vol 166 (1) ◽

pp. 121-131 ◽

Cited By ~ 192

Author(s):

Julia M. Edgar ◽

Mark McLaughlin ◽

Donald Yool ◽

Su-Chun Zhang ◽

Jill H. Fowler ◽

...

Keyword(s):

Mouse Model ◽

Axonal Transport ◽

Hereditary Spastic Paraplegia ◽

Progressive Multiple Sclerosis ◽

Spastic Paraplegia ◽

Fast Axonal Transport ◽

Anterograde Transport ◽

Local Regulation ◽

Protein Subunits

Oligodendrocytes are critical for the development of the plasma membrane and cytoskeleton of the axon. In this paper, we show that fast axonal transport is also dependent on the oligodendrocyte. Using a mouse model of hereditary spastic paraplegia type 2 due to a null mutation of the myelin Plp gene, we find a progressive impairment in fast retrograde and anterograde transport. Increased levels of retrograde motor protein subunits are associated with accumulation of membranous organelles distal to nodal complexes. Using cell transplantation, we show categorically that the axonal phenotype is related to the presence of the overlying Plp null myelin. Our data demonstrate a novel role for oligodendrocytes in the local regulation of axonal function and have implications for the axonal loss associated with secondary progressive multiple sclerosis.

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