Hereditary spastic paraplegia

Murala, Sireesha; Nagarajan, Elanagan; Bollu, Pradeep C.

doi:10.1007/s10072-020-04981-7

Cited by 62 publications

(60 citation statements)

References 36 publications

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“…However, patients may also present additional neurologic and non-neurologic symptoms. 1 Patients with HSP share axon degeneration, mainly in the thoracic and distal spinal cord, and a reduced affectation of the cervical cord, implying affectations of both motor neurons with different degrees of severity. 2 HSP has a low frequency, between 3 and 10/100,000 depending on the population, and has been associated with mutations or gene variants in at least 73 different genes.…”

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confidence: 99%

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Dysfunctional Homozygous VRK1-D263G Variant Impairs the Assembly of Cajal Bodies and DNA Damage Response in Hereditary Spastic Paraplegia

et al. 2021

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Background and ObjectivesTo conduct a genetic and molecular functional study of a family with members affected of hereditary spastic paraplegia (HSP) of unknown origin and carrying a novel pathogenic vaccinia-related kinase 1 (VRK1) variant.MethodsWhole-exome sequencing was performed in 2 patients, and their parents diagnosed with HSP. The novel VRK1 variant was detected by whole-exome sequencing, molecularly modeled and biochemically characterized in kinase assays. Functionally, we studied the role of this VRK1 variant in DNA damage response and its effect on the assembly of Cajal bodies (CBs).ResultsWe have identified a very rare homozygous variant VRK1-D263G with a neurologic phenotype associated with HSP and moderate intellectual disability. The molecular modeling of this VRK1 variant protein predicted an alteration in the folding of a loop that interferes with the access to the kinase catalytic site. The VRK1-D263G variant is kinase inactive and does not phosphorylate histones H2AX and H3, transcription factors activating transcription factor 2 and p53, coilin needed for assembly of CBs, and p53 binding protein 1, a DNA repair protein. Functionally, this VRK1 variant protein impairs CB formation and the DNA damage response.DiscussionThis report expands the neurologic spectrum of neuromotor syndromes associated with a new and rare VRK1 variant, representing a novel pathogenic participant in complicated HSP and demonstrates that CBs and the DNA damage response are impaired in these patients.

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confidence: 99%

“… 2 HSP has a low frequency, between 3 and 10/100,000 depending on the population, and has been associated with mutations or gene variants in at least 73 different genes. 1 , 3 …”

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confidence: 99%

Dysfunctional Homozygous VRK1-D263G Variant Impairs the Assembly of Cajal Bodies and DNA Damage Response in Hereditary Spastic Paraplegia

et al. 2021

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“…Worldwide, the estimated prevalence of autosomal dominant HSP, representing 75-80% of all HSPs, is 0.5-5.5/100,000, with SPG4 accounting for 60% of autosomal dominant and 45% of pure HSPs. 4,5,30 KPNA3 variants seem to be a rare cause of HSP, because Sanger sequencing of all exons of KPNA3 in 102 patients with early-onset pure HSP did not reveal additional subjects with variants in this gene. In fact, the vast majority of known HSP disease genes are mutated in a rather small proportion of patients, underscoring the need for extended gene-panel and/or exome analysis as a preferred diagnostic procedure.…”

Section: Discussionmentioning

confidence: 95%

“…5 Autosomal dominant inheritance is the prevailing form of transmission in pure HSP. 4 Among the nonhereditary causes of spasticity, cerebral palsy (CP) may pose specific difficulties for differential diagnosis, especially in sporadic cases with early infantile onset of disease. 6 Although variants in >80 genes or loci have been shown to be associated with HSP, 1,3,4,7 there is still a considerable number of patients with no pathogenic variant in any of the known HSP-associated genes.…”

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confidence: 99%

Dominant KPNA3 Mutations Cause Infantile‐Onset Hereditary Spastic Paraplegia

Schob

Hempel

Brožková

et al. 2021

Annals of Neurology

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Objective: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lowerextremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantileonset form of HSP in a cohort of 8 patients with a uniform clinical presentation. Methods: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. Results: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. Interpretation: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP.

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“…The clinical manifestations are mainly progressive spastic gait, increased muscle tension at rest of both lower limbs, hyperreflexia of the tendon, clonic spasms of the ankle, positive pathological signs, and myasthenia gravis, possibly accompanied by abnormal bladder and rectal function, ankle joint vibration loss, clawfoot, and scoliosis (2,3). HSP can start before 35 years of age (early onset) or after 35 years of age (classical) and can classified as pure (uncomplicated) and complicated (complex) based on signs and symptoms, according to Harding's criteria outlined in 1981 and 1983 (2,(4)(5)(6). The pure form is confined to the progressive spastic paresis with clinical manifestations restricted to corticospinal system degeneration, including lower extremity weakness and spasticity, corticospinal tract signs, disturbance in vibration sense and proprioception, and a variable hypertonic urinary disturbance (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

Shen¹,

Zhang²,

Li³

et al. 2022

Ann Transl Med

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Background: Hereditary spastic paraplegia (HSP) is a rare group of genetically heterogeneous, neurodegenerative disorders. The aim of this study was to identify pathological candidate genes and variants in a large pedigree cohort of 11 purely HSP patients in Yunnan Province.Methods: Whole-exome sequencing (WES) was applied to 2 HSP patients and 1 control patient to screen out the candidate gene variants. Then, filtration and verification of these pathological variants were performed by Sanger sequencing.Results: After the raw data were filtered, two genes with novel variations (SPAST: c.1510 C>T, p.Gln504X, RefSeq.NM_199436; DNAJC16: c.718 C>T, p.Q240X, Ref Seq NM_015291) were identified. The accession numbers of the genes in the ClinVar database were SCV001573094 and SCV001573804, respectively. One gene with a reported single nucleotide polymorphism (CPT1C: rs150853576) was filtered as a candidate variant. Using Sanger sequencing, the novel SPAST gene (protein: Spastin) variant leading to a predicted premature termination and an 18% deletion of the SPAST/spastic paraplegia type 4 (SPG4) protein was confirmed to exist only in affected individuals. The candidate CPT1C and DNAJC16 variants were verified in almost all HSP patients, with one exception.Conclusions: Considering that the clinical symptoms and time of onset of HSP are highly heterogeneous, the SPAST as a genotype-phenotype cosegregated variant might be the causative gene of this pedigree, and the other two variants might present cumulative risks to the occurrence and progression of HSP. These three candidate genes with or without novel variants may be potential contributors to disease onset, and therefore useful diagnostic and therapeutic biomarkers. Further research is required to confirm the functions of these genes.

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Hereditary spastic paraplegia

Cited by 62 publications

References 36 publications

Dysfunctional Homozygous VRK1-D263G Variant Impairs the Assembly of Cajal Bodies and DNA Damage Response in Hereditary Spastic Paraplegia

Dysfunctional Homozygous VRK1-D263G Variant Impairs the Assembly of Cajal Bodies and DNA Damage Response in Hereditary Spastic Paraplegia

Dominant KPNA3 Mutations Cause Infantile‐Onset Hereditary Spastic Paraplegia

A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

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