Characterization of Zebrafish Models of Marinesco-Sjögren Syndrome

Kawahara, Genri; Hayashi, Yukiko

doi:10.1371/journal.pone.0165563

Cited by 11 publications

(13 citation statements)

References 21 publications

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“… 11 Therefore, we hypothesized that a mutation in CHP1, as a crucial regulator of NHE1, 6 , 7 could impair expression and targeting of the exchanger, resembling the pathogenesis in mice and humans. Taking advantage of the zebrafish model system for modeling ARCAs, 12 – 14 we generated a chp1- deficient zebrafish, which not only resembled the clinical features of the affected siblings but also corroborates the pathogenicity of the CHP1 hypomorphic Lys19del mutation in vitro and in vivo.…”

mentioning

confidence: 57%

Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function

et al. 2018

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Objective: To ascertain the genetic and functional basis of complex autosomal recessive cerebellar ataxia (ARCA) presented by 2 siblings of a consanguineous family characterized by motor neuropathy, cerebellar atrophy, spastic paraparesis, intellectual disability, and slow ocular saccades.Methods: Combined whole-genome linkage analysis, whole-exome sequencing, and focused screening for identification of potential causative genes were performed. Assessment of the functional consequences of the mutation on protein function via subcellular fractionation, sizeexclusion chromatography, and fluorescence microscopy were done. A zebrafish model, using Morpholinos, was generated to study the pathogenic effect of the mutation in vivo.Results: We identified a biallelic 3-bp deletion (p.K19del) in CHP1 that cosegregates with the disease. Neither focused screening for CHP1 variants in 2 cohorts (ARCA: N 5 319 and NeurOmics: N 5 657) nor interrogating GeneMatcher yielded additional variants, thus revealing the scarcity of CHP1 mutations. We show that mutant CHP1 fails to integrate into functional protein complexes and is prone to aggregation, thereby leading to diminished levels of soluble CHP1 and reduced membrane targeting of NHE1, a major Na 1 /H 1 exchanger implicated in syndromic ataxiadeafness. Chp1 deficiency in zebrafish, resembling the affected individuals, led to movement defects, cerebellar hypoplasia, and motor axon abnormalities, which were ameliorated by coinjection with wild-type, but not mutant, human CHP1 messenger RNA. Conclusions: Collectively, our results identified CHP1 as a novel ataxia-causative gene in humans,further expanding the spectrum of ARCA-associated loci, and corroborated the crucial role of NHE1 within the pathogenesis of these disorders. Neurol Genet 2018;4:e209; doi: 10.1212/ NXG.0000000000000209 GLOSSARY ARCA 5 autosomal recessive cerebellar ataxia; CaP-MN 5 caudal primary motor neuron; cDNA 5 complementary DNA; EGFR 5 epidermal growth factor receptor; GFP 5 green fluorescent protein; HMW 5 high molecular weight; HPRT 5 hypoxanthine-guanine phosphoribosyltransferase; HSP90 5 heat shock protein 90; KO 5 knockout; LKS 5 LichtensteinKnorr syndrome; LOD 5 Logarithm of the odds; mRNA 5 messenger RNA; MO 5 Morpholino; OE 5 overexpression; RT-PCR 5 reverse transcription PCR; SEC 5 size-exclusion chromatography; WB 5 Western blot; WES 5 whole-exome sequencing; WT 5 wild type.Autosomal recessive cerebellar ataxias (ARCAs) comprise a heterogeneous group of neurodegenerative disorders associating cerebellar degeneration to a variable combination of central or peripheral neurologic or nonneurologic signs.1 Collectively, ARCAs have an estimated frequency of 1:20,000 and often show overlapping features with spastic paraplegias and peripheral neuropathies.

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confidence: 57%

Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function

et al. 2018

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“…Schwann cells were unaffected. The number of PCs were significantly reduced, and the eyes were smaller than in control animals . Finally, western blot analysis showed up‐regulation of BiP, lipidated LC3 and activated caspase 3, indicative of UPR, autophagy and apoptosis .…”

Section: Zebrafish With Reduced Sil1 Expression Model Some Aspects Ofmentioning

confidence: 91%

Section: Zebrafish With Reduced Sil1 Expression Model Some Aspects Ofmentioning

confidence: 99%

“…The key features of MSS were recapitulated by silencing Sil1 expression in the zebrafish Danio rerio . Antisense morpholino oligonucleotides targeting two splice regions of Sil1 reduced expression of Sil1 protein in the zebrafish embryo by about 50% . Examination by birefringence assay and immunostaining with antibodies against beta‐dystroglycan, myosin heavy chain and synaptic vesicle protein 2, and staining with fluorescent alpha‐bungarotoxin showed abnormalities in myofibers and neuromuscular junctions .…”

Section: Zebrafish With Reduced Sil1 Expression Model Some Aspects Ofmentioning

confidence: 99%

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Review: Protein misfolding diseases – the rare case of Marinesco‐Sjögren syndrome

Chiesa

Sallese

2020

Neuropathology Appl Neurobio

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Secretory and cell membrane proteins are synthesized in the endoplasmic reticulum (ER), where a network of molecular chaperones and folding factors ensure correct protein folding and export to post‐ER compartments. Failure of this process leads to accumulation of unfolded/misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), a complex signalling pathway aimed at restoring ER homeostasis, whose failure eventually leads to cell death. Suppressor of Ire1/Lhs1 double mutant (SIL1) is a nucleotide exchange factor for immunoglobulin binding protein, the main ER chaperone and primary sensor of ER stress. Loss of SIL1 function causes Marinesco‐Sjögren syndrome (MSS), a rare multisystem disease of early infancy for which there is no cure. This review, examines the current understanding of SIL1 activities in the ER, and reviews experimental data describing the consequences of SIL1 deficiency in cell and animal models. We discuss the evidence supporting a role of the UPR – particularly the protein kinase RNA‐like endoplasmic reticulum kinase branch – in the pathogenesis of MSS, and how this may be pharmacologically manipulated for treatment.

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“…Some MSS patients present with additional Dandy-Walker syndrome [9], spastic paraplegia [10] or motor neuronopathy associated with bradykinetic movement disorder [11]. Moreover, Sil1 knock down in zebrafish by two different antisense oligo morpholinos resulted in loss of Purkinje cells [33]. Hence, a profound role of SIL1 in neuronal function and maintenance can be postulated.…”

Section: Pns Is Vulnerable Against the Loss Of Sil1mentioning

confidence: 99%

SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human

Phan

Cox

Cipriani

et al. 2019

Neurobiology of Disease

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Characterization of Zebrafish Models of Marinesco-Sjögren Syndrome

Cited by 11 publications

References 21 publications

Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function

Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function

Review: Protein misfolding diseases – the rare case of Marinesco‐Sjögren syndrome

SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human

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