Expansion of the genetic landscape of <i>ERLIN2</i>‐related disorders

Srivastava, Siddharth; D’Amore, Angelica; Cohen, Julie S.; Swanson, Lindsay C.; Ricca, Ivana; Pini, Antonella; Fatemi, Ali; Ebrahimi‐Fakhari, Darius; Santorelli, Filippo M.

doi:10.1002/acn3.51007

Cited by 15 publications

(10 citation statements)

References 28 publications

(38 reference statements)

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“…To date, eight AR‐SPG18 families, five AD‐SPG18 families, and three sporadic cases have been reported (Alazami et al, 2011; Al‐Saif et al, 2012; Amador et al, 2019; Park et al, 2020; Rydning et al, 2018; Srivastava et al, 2020; Tian et al, 2016; Wakil et al, 2013; Yildirim et al, 2011) (Table 1). Patients were distributed in Middle East, Turkey, China, Korea, France, and Norway.…”

Section: Resultsmentioning

confidence: 99%

“…Two cases had the heterozygous mutations. Another case had the homozygous missense mutation due to uniparental disomy and presented an earlier onset at 2 years of age (Srivastava et al, 2020).…”

Section: Summary Of Spg18 Families/casesmentioning

confidence: 99%

“…To date, eight AR-SPG18 families, five AD-SPG18 families, and three sporadic cases have been reported (Alazami et al, 2011;Al-Saif et al, 2012;Amador et al, 2019;Park et al, 2020;Rydning et al, 2018;Srivastava et al, 2020;Tian et al, 2016;Wakil et al, 2013;Yildirim et al, 2011) Only one Chinese family with the compound heterozygous mutations presented as pure HSP. Other superimposed manifestations include limb deformities, language and intellectual impairment, epilepsy, lower motor neuron signs, and deafness.…”

Section: Summary Of Spg18 Families/casesmentioning

confidence: 99%

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More autosomal dominant SPG18 cases than recessive? The first AD‐SPG18 pedigree in Chinese and literature review

Chen

Zou

et al. 2021

Brain and Behavior

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Objective: Hereditary spastic paraplegia (HSP) due to ERLIN2 gene mutations was designated as spastic paraplegia 18 (SPG18). To date, SPG18 families/cases are still rarely reported. All early reported cases shared the autosomal recessive (AR) inheritance pattern. Over the past 3 years, autosomal dominant (AD) or sporadic SPG18 cases had been continuously reported. Here, we reported the clinical and genetic features of the first autosomal dominant SPG18 pedigree in Chinese. Methods:We conducted detailed medical history inquiry, neurological examinations of the proband and his family members, and charted the family tree. The proband underwent brain and cervical magnetic resonance imaging (MRI), electromyography (EMG), and whole exome sequencing. Sanger sequencing was performed to verify the genetic variation in the proband and some family members. A literature review of all reported SPG18 families/cases was carried out to summarize the clinical-genetic characteristics of SPG18 under different inheritance patterns.Results: Four patients were clinically diagnosed as chronic spastic paraplegia in three consecutive generations with the autosomal dominant inheritance model. All the patients presented juvenile-adolescent onset and gradually worsening pure HSP phenotype. Clinical phenotypes were consistent within the family. Whole exome sequencing in the proband identified a previously reported heterozygous c.502G > A (p.V168M) mutation in exon 8 of ERLIN2 gene. This mutation was cosegregated with the phenotype in the family and was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. To date, eight AR-SPG18 families, five AD-SPG18 families, and three sporadic cases had been reported. Clinical phenotype of AD-SPG18 was juvenile-adolescent onset pure HSP, while the phenotype of AR-SPG18 was mostly complicated HSP with earlier onset and more severe conditions. In rare cases, the initial spastic paraplegia could evolve to rapidly progressive amyotrophic lateral sclerosis (ALS). Conclusions:We reported the first autosomal dominant SPG18 pedigree in Chinese Han population, which added more pathogenic evidence for V168M mutation. As moreThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Resultsmentioning

confidence: 99%

Section: Summary Of Spg18 Families/casesmentioning

confidence: 99%

Section: Summary Of Spg18 Families/casesmentioning

confidence: 99%

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More autosomal dominant SPG18 cases than recessive? The first AD‐SPG18 pedigree in Chinese and literature review

Chen

Zou

et al. 2021

Brain and Behavior

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“…This lncRNA gene, not previously related to MS, is described as a novel transcript antisense to the ERLIN2 gene. The misfunction of ERLIN2, which mediates intracellular calcium signaling and participates in neurodevelopment and neurotransmission, leads to motor disorders and spastic paraplegia [83, 84]. Importantly, ERLIN2 mutations lead to abnormal splicing and nonsense-mediated mRNA decay, promoting motor neurodegeneration and juvenile amyotrophic lateral sclerosis [55].…”

Section: Discussionmentioning

confidence: 99%

A Deep Transcriptome Meta-Analysis Reveals Sex-based Molecular Differences in Multiple Sclerosis

Català-Senent

Andreu

Roig

et al. 2021

Preprint

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Background: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory, and degenerative disease of the central nervous system that affects both women and men but the risk of developing MS is higher in women (2-3:1 ratio compared to men). Current knowledge does not allow a precise definition of the sex-related factors intervening in MS. Here, we explore the role of sex in this neurodenegerative disease to identify molecular mechanisms underlying sex-based diferences that can guide novel therapeutics approaches aimed for men and women. Methods: We performed a rigorous and systematic review of MS whole transcriptome studies that included sex patient information in Gene Expression Omnibus and ArrayExpress databases, following PRISMA statment guidelines. A differential gene expression (DGE) was performed for each selected study. Then, three meta-analyses based on genes and different contrasts were addressed to evaluate common features and sex bias in all scenarios: one meta-analysis in nervous tissue studies (4), another in blood studies (5), and a third that integrated the studies from both tissues, blood and nervous system (9). Finally, a gene set analysis (GSA) was performed on the meta-analyzed differential transcriptomic profile between women and men, to study their involvement in biological pathways and phenotypes (physiological and pathological states) sex related. Results: After screening 122 publications, the systematic review provided a selection of nine studies (5 in blood and 4 in nervous tissue) with a total of 653 samples (269 MS women, 152 control women, 116 MS men, 116 control men). The blood sex-differences gene meta-analysis identified 1 gene overexpressed in women (KIR2DL3) while gene meta-analysis in the nervous tissue resulted in 5 genes differentially expressed (4 overexpressed in women: C7orf73, CECR7, TRAF3IP2-AS1, ZNF117; and 1 overexpressed in men: HIST1H2AE). In the global meta-analysis (blood and nervous tissue), 1 gene involved in sex differences were detected (more expressed in women: LOC102723701). 9 MS biomarkers were also identified in both sexes (4 overexpressed genes in MS patients: HIST1H2BC, SMEK2, STBD1, TMEM140) and 5 down-regulated in MS patients: C16orf59, C20orf177, C9orf23, FAM65B, PKI55). Additionally, the GSA related to gene meta-analysis revealed a set of functions differentially enriched in men and women, in the different analysed tissues. Conclusion: These findings provide valuable opportunities for better understanding of MS related sex differences and develop effective and sex-specific interventions down further studies.

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“…Elucidating how ERLIN complexes interact with different E3-ubiquitin ligases and which cellular processes are controlled by the ERLIN complexes is crucial, since mutations in ERLIN1 or ERLIN2 gene have been associated with motoneuronal diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis, and amyotrophic lateral sclerosis (ALS) (Al-Saif et al, 2012; Alazami et al, 2011; Kume et al, 2021; Park et al, 2020; Qiao et al, 2022; Rydning et al, 2018; Srivastava et al, 2020; Tunca et al, 2018; Wakil et al, 2013; Yildirim et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway

Veronese,

Kallabis,

Kaczmarek

et al. 2024

Preprint

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Complexes of ERLIN1 and ERLIN2 form large ring-like cup-shaped structures on the endoplasmic reticulum (ER) membrane and serve as platforms to bind cholesterol and E3-ubiquitin ligases, potentially defining functional nanodomains. Here, we show that ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 and RNF170. We identify a luminal N-terminal conserved region in TMUB1 and RNF170 required for this interaction. Three-dimensional modelling shows that this conserved motif binds the SPFH domain of two adjacent ERLIN subunits at different interfaces. Protein variants that preclude these interactions have been previously linked to hereditary spastic paraplegia (HSP). By using omics approaches in combination with phenotypic characterisation of cells lacking both ERLINs, we demonstrate a role for ERLIN scaffolds in maintaining cholesterol levels in the ER by favouring transport to the Golgi over esterification, thereby regulating Golgi morphology and the secretory pathway.

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Expansion of the genetic landscape of ERLIN2‐related disorders

Cited by 15 publications

References 28 publications

More autosomal dominant SPG18 cases than recessive? The first AD‐SPG18 pedigree in Chinese and literature review

More autosomal dominant SPG18 cases than recessive? The first AD‐SPG18 pedigree in Chinese and literature review

A Deep Transcriptome Meta-Analysis Reveals Sex-based Molecular Differences in Multiple Sclerosis

ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway

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