Variation in <i>SIPA1L2</i> is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Tao, Feifei; Beecham, Gary W.; Rebelo, Adriana P.; Svaren, John; Blanton, Susan H.; Moran, John J.; Lopez‐Anido, Camila; Morrow, Jasper M.; Abreu, Lisa; Rizzo, Devon; Kirk, Callyn A.; Wu, Xingyao; Feely, Shawna; Verhamme, Camiel; Saporta, Mario; Herrmann, David N.; Day, John W.; Sumner, Charlotte J.; Lloyd, Thomas E.; Li, Jun; Yum, Sabrina W.; Taroni, Franco; Baas, Frank; Choi, Byung‐Ok; Pareyson, Davide; Scherer, Steven S.; Reilly, Mary M.; Shy, Michael E.

doi:10.1002/ana.25426

Cited by 37 publications

(36 citation statements)

References 51 publications

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“…This is also true for different variants of the amino acid adjacent to the p.Asp411Gly variant we have reported here, where p.Glu412Gly causes both demyelinating CMT1D 12 and axonal CMT 14 , and p.Glu412Lys causes DSN 35 . Given these observations, it is possible that additional genetic factors exist which modify the phenotype of EGR2 variant, such as those recently reported for CMT1A 37 .…”

Section: Discussionmentioning

confidence: 92%

A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

Grosz

Golovchenko

Ellis

et al. 2019

Sci Rep

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EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant. Charcot-Marie-Tooth (CMT) neuropathy is group of degenerative motor and sensory peripheral neuropathies which are clinically and genetically heterogenous. Pathogenic variants in over 90 genes cause CMT, and whole-exome sequencing (WES) is now an effective tool for screening known causative genes in unsolved CMT families. Pathogenic variants in the EGR2 gene (early growth response 2) cause a broad spectrum of peripheral neuropathy phenotypes. This includes two forms of severe early-onset peripheral neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3) 1-3 and congenital hypomyelinating neuropathy (CHN/CMT4E) 4,5 , as well as adult-onset demyelinating CMT1D with mild-moderate symptoms 3-12 and variable-onset axonal CMT with varied symptom severity 13,14. EGR2 encodes a C 2 H 2-type zinc-finger transcription factor that regulates the expression of genes involved in the formation and maintenance of myelin, including GJB1 (gap junction beta 1), MPZ (myelin protein zero), MBP (myelin basic protein), MAG (myelin associated glycoprotein), PRX (periaxin), and PMP22 (peripheral myelin protein 22) 4,15-18. Approximately half of the reported disease-associated EGR2 variants are de novo and are associated with a severe phenotype 13. Here, we report a sporadic de novo EGR2 variant in the third zinc-finger domain, c.1232A > G p.Asp411Gly, discovered through WES candidate gene screening. This variant manifested as a severe DSN phenotype with early onset at two years of age.

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Section: Discussionmentioning

confidence: 92%

A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

Grosz

Golovchenko

Ellis

et al. 2019

Sci Rep

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“…Finally, RT induced gene expression of both SIPA1L (signal-induced proliferation associated 1 like)2 and LOXHD (lipoxygenase homology domains)1, genomic variants in which are associated with PD in previous studies (Safaralizadeh et al, 2016;Wang et al, 2016;Gaare et al, 2018;Tao et al, 2019). Presently, there is no available evidence of single-nucleotide polymorphisms in these genes contributing to differential expression in healthy skeletal muscle tissue.…”

Section: Genes Linked To Pd Pathologymentioning

confidence: 94%

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

Lavin

Sealfon

et al. 2020

Front. Physiol.

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Parkinson's disease (PD) is the most common motor neurodegenerative disease, and neuromuscular function deficits associated with PD contribute to disability. Targeting these symptoms, our laboratory has previously evaluated 16-week high-intensity resistance exercise as rehabilitative training (RT) in individuals with PD. We reported significant improvements in muscle mass, neuromuscular function (strength, power, and motor unit activation), indices of neuromuscular junction integrity, total and motor scores on the unified Parkinson's disease rating scale (UPDRS), and total and sub-scores on the 39-item PD Quality of Life Questionnaire (PDQ-39), supporting the use of RT to reverse symptoms. Our objective was to identify transcriptional networks that may contribute to RT-induced neuromuscular remodeling in PD. We generated transcriptome-wide skeletal muscle RNA-sequencing in 5 participants with PD [4M/1F, 67 ± 2 years, Hoehn and Yahr stages 2 (n = 3) and 3 (n = 2)] before and after 16-week high intensity RT to identify transcriptional networks that may in part underpin RT-induced neuromuscular remodeling in PD. Following RT, 304 genes were significantly upregulated, notably related to remodeling and nervous system/muscle development. Additionally, 402 genes, primarily negative regulators of muscle adaptation, were downregulated. We applied the recently developed Pathway-Level Information ExtractoR (PLIER) method to reveal coordinated gene programs (as latent variables, LVs) that differed in skeletal muscle among young (YA) and old (OA) healthy adults and PD (n = 12 per cohort) at baseline and in PD pre-vs. post-RT. Notably, one LV associated with angiogenesis, axon guidance, and muscle remodeling was significantly lower in PD than YA at baseline and was significantly increased by exercise. A different LV annotated to denervation, autophagy, and apoptosis was increased in both PD and OA relative to YA and was also reduced by 16-week RT in PD. Thus, this analysis identified two novel skeletal

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“…Identifying genetic modifiers is challenging as it often requires large sample sizes, but this problem can be overcome with the use of extreme phenotype sampling (EPS)a technique that focuses on alleles that tend to associate with one phenotypic extreme rather than random sampling 49 . This approach was used in a well-designed genome-wide genotyping study on a large sample of 330 deeply phenotyped patients with CMT1A who were of European ancestry 50 . This study identified the SIPA1L2 gene as a genetic modifier of ankle dorsiflexion weakness, a hallmark feature of CMT.…”

Section: Whole-genome Sequencingmentioning

confidence: 99%

Next-generation sequencing in Charcot–Marie–Tooth disease: opportunities and challenges

2019

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Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine, and as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing (WES), wholegenome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify 2 structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.

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Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Cited by 37 publications

References 51 publications

A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

Next-generation sequencing in Charcot–Marie–Tooth disease: opportunities and challenges

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