Author Correction: Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Cortese, Andrea; Züchner, Stephan; Negri, Sara; Courel, Steve; Abreu, Lisa; Bacon, Chelsea; Bai, Yunhong; Bis-Brewer, Dana M.; Bugiardini, Enrico; Buglo, Elena; Danzi, Matt C.; Feely, Shawna; Athanasiou-Fragkouli, Alkyoni; Haridy, Nourelhoda A.; Isasi, Rosario; Khan, Alaa; Laurá, Matilde; Magri, Stefania; Pipis, Menelaos; Pisciotta, Chiara; Powell, Eric; Rossor, Alexander M.; Saveri, Paola; Sowden, Janet E.; Tozza, Stefano; Vandrovcová, Jana; Dallman, Julia E.; Grignani, Elena; Marchioni, Enrico; Scherer, Steven S.; Tang, Beisha; Lin, Zhi Xiu; Al-Ajmi, Abdullah; Schüle, Rebecca; Synofzik, Matthis; Maisonobe, Thierry; Stojkovic, Tanya; Auer‐Grumbach, Michaela; Abdelhamed, Mohamed A.; Hamed, Sherifa A.; Zhang, Ruxu; Manganelli, Fiore; Santoro, Lucio; Taroni, Franco; Pareyson, Davide; Houlden, Henry; Herrmann, David N.; Shy, Michael E.; Zhai, R. Grace

doi:10.1038/s41588-020-0649-7

Cited by 20 publications

(65 citation statements)

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“…13 ). The p.A253Qfs*27 in SORD was also previously overlooked likely due to technical reasons, although in that case it was likely due to a highly homologous pseudogene ( Cortese et al. , 2020 ).…”

Section: Discussionmentioning

confidence: 99%

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy

Pagnamenta¹,

Kaiyrzhanov²,

Zou³

et al. 2021

Brain

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The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6–83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

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Section: Discussionmentioning

confidence: 99%

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy

Pagnamenta¹,

Kaiyrzhanov²,

Zou³

et al. 2021

Brain

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“…We previously observed the age-dependent formation of vacuole-like structures in Sord-deficient flies by labeling neuronal membranes with horseradish peroxidase (HRP), indicating a progressive loss of synaptic terminals (1). We also reported a reduced level of synaptic active zone marker Bruchpilot (BRP), indicating synaptic degeneration (1).…”

Section: At-007 Ameliorates Synaptic Degeneration In Sord-deficient F...mentioning

confidence: 97%

“…To evaluate axonal and synaptic integrity, we took advantage of the Drosophila visual system, where the photoreceptor neurons are highly organized in parallel columns and make synapses with lamina monopolar cells (13). We previously observed the age-dependent formation of vacuole-like structures in Sord-deficient flies by labeling neuronal membranes with horseradish peroxidase (HRP), indicating a progressive loss of synaptic terminals (1). We also reported a reduced level of synaptic active zone marker Bruchpilot (BRP), indicating synaptic degeneration (1).…”

Section: At-007 Ameliorates Synaptic Degeneration In Sord-deficient F...mentioning

confidence: 99%

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Sorbitol reduction via govorestat ameliorates synaptic dysfunction and neurodegeneration in sorbitol dehydrogenase deficiency

Zhu¹,

Lobato²,

Rebelo³

et al. 2023

JCI Insight

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“…The recent identification of recessive mutations in SORD represents a promising therapeutic opportunity [116]. SORD neuropathy is a motor-predominant, axonal neuropathy, [116], and may be the most common cause of recessively inherited peripheral neuropathy. SORD encodes sorbitol dehydrogenase, the second step in the polyol pathway that enzymatically converts glucose to fructose.…”

Section: Sord Neuropathymentioning

confidence: 99%

Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities

McCray

Scherer

2021

Neurotherapeutics

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Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.

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Author Correction: Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Cited by 20 publications

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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy

Sorbitol reduction via govorestat ameliorates synaptic dysfunction and neurodegeneration in sorbitol dehydrogenase deficiency

Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities

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