A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis

Zivony-Elboum, Yifat; Westbroek, Wendy; Kfir, Nehama Cohen; Savitzki, David; Shoval, Yishay; Bloom, Assnat; Rod, Raya; Khayat, Morad; Gross, Bella; Samri, Walid; Cohen, Hector; Sonkin, Vadim; Freidman, Tatiana; Geiger, Dan; Fattal‐Valevski, Aviva; Anikster, Yair; Waters, Aoife; Kleta, Robert; Falik‐Zaccai, Tzipora C.

doi:10.1136/jmedgenet-2012-100742

Cited by 75 publications

(38 citation statements)

References 40 publications

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“…A homozygous mutation in SPG53/VPS37A (vacuolar protein sorting 37A), a member of the endosomal sorting complex required for transport (ESCRT) system, has been described in a complicated HSP (Zivony-Elboum et al, 2012). The system plays a central role in intracellular trafficking, maturation of multivesicular bodies, and sorting of ubiquitinated membrane proteins into internal luminal vesicles (Raiborg and Stenmark, 2009).…”

Section: Spg53mentioning

confidence: 99%

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

Giudice

Lombardi

Santorelli

et al. 2014

Experimental Neurology

294

278

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Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by pathophysiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. The prominent features of this pathological condition are progressive spasticity and weakness of the lower limbs. To date, 72 spastic gait disease-loci and 55 spastic paraplegia genes (SPGs) have been identified. All modes of inheritance (autosomal dominant, autosomal recessive, and X-linked) have been described. Recently, a late onset spastic gait disorder with maternal trait of inheritance has been reported, as well as mutations in genes not yet classified as spastic gait disease. Several cellular processes are involved in its pathogenesis, such as membrane and axonal transport, endoplasmic reticulum membrane modeling and shaping, mitochondrial function, DNA repair, autophagy, and abnormalities in lipid metabolism and myelination processes. Moreover, recent evidences have been found about the impairment of endosome membrane trafficking in vesicle formation and about the involvement of oxidative stress and mtDNA polymorphisms in the onset of the disease. Interactome networks have been postulated by bioinformatics and biological analyses of spastic paraplegia genes, which would contribute to the development of new therapeutic approaches.

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Section: Spg53mentioning

confidence: 99%

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

Giudice

Lombardi

Santorelli

et al. 2014

Experimental Neurology

294

278

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“…pnpla6 ( SPG39 ) knockdown resulted in developmental abnormalities and motor neuron defects, including axon truncation and branching (Song et al, 2013). A loss of motility was induced in vps37a (Vacuolar protein sorting 37A; SPG53 ) knockdown zebrafish larvae (Zivony-Elboum et al, 2012). In a number of cases, these deficits could be rescued using the human orthologous mRNA transcript, but not using the disease-causing mRNA transcript, arguing for loss, rather than toxic gain, of function.…”

Section: Hereditary Spastic Paraplegia (Hsp)mentioning

confidence: 99%

Fishing for causes and cures of motor neuron disorders

Patten

Armstrong

Lissouba

et al. 2014

Disease Models &Amp; Mechanisms

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Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

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“…Supporting this model, in Farazi Fard et al, it was demonstrated that truncated UBAP1 protein was able to colocalize and bind to its binding partner VSP28 but was unable to bind to ubiquitinated proteins, corroborating the dominant‐negative disease mechanism. Interestingly, one of the selective assembly partners of UBAP1 for the ESCRT‐I protein complex, VPS37A, is known to be associated with AR spastic paraplegia 53 (SPG53; MIM# 614898; Zivony‐Elboum et al, ), lending further credence to the potential pathogenicity of deleterious variants in UBAP1 in causing HSP.…”

Section: Discussionmentioning

confidence: 99%

Truncating variants in UBAP1 associated with childhood‐onset nonsyndromic hereditary spastic paraplegia

Chen

Rosenfeld

et al. 2019

Human Mutation

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Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex. K E Y W O R D S autosomal dominant, escape of nonsense-mediated decay, hereditary spastic paraplegia, UBAP1

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A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis

Cited by 75 publications

References 40 publications

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

Fishing for causes and cures of motor neuron disorders

Truncating variants in UBAP1 associated with childhood‐onset nonsyndromic hereditary spastic paraplegia

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