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New MORC2 gene mutations are associated with distinctive features: from axonal neuropathy to late adult-onset spinal muscular atrophy like phenotype
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  • Arnaud Jacquier,
  • Shams Ribault,
  • Michel Mendes,
  • Nicolas Lacoste,
  • Valérie Risson,
  • Julien Carras,
  • Philippe Latour,
  • Aleksandra Nadaj-Pakleza,
  • Tanya Stojkovic,
  • Laurent Schaeffer
Arnaud Jacquier
Universite Claude Bernard Lyon 1 - Domaine de Rockefeller

Corresponding Author:[email protected]

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Shams Ribault
Universite Claude Bernard Lyon 1 - Domaine de Rockefeller
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Michel Mendes
Centro Hospitalar de Tras-os-montes e Alto Douro EPE
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Nicolas Lacoste
Universite Claude Bernard Lyon 1 - Domaine de Rockefeller
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Valérie Risson
Universite Claude Bernard Lyon 1 - Domaine de Rockefeller
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Julien Carras
Universite Claude Bernard Lyon 1 - Domaine de Rockefeller
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Philippe Latour
Universite Claude Bernard Lyon 1 - Domaine de Rockefeller
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Aleksandra Nadaj-Pakleza
Hopitaux universitaires de Strasbourg Centre de reference des maladies neuromusculaires d'origine genetique de l'enfant et de l'adulte
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Tanya Stojkovic
Hopital Pitie-Salpetriere Departement de Neuropathologie
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Laurent Schaeffer
Universite Claude Bernard Lyon 1 - Domaine de Rockefeller
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Abstract

MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like (SMA-like) with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge. Here we report the characterization of an in vitro model to evaluate the pathogenicity of variants of unknown significance based on MORC2 overexpression in a neuroblastoma cell line SH-EP or in cortical neurons. Likewise, we show that MORC2 mutants affect survival and trigger apoptosis over time in SH-EP cell line. Furthermore, overexpression in primary cortical neurons increases apoptotic cell death and decreases neurite outgrowth. Altogether, these approaches establish the pathogenicity of two new variants p.G444R and p.H446Q in three patients from two families. These new mutations in MORC2 gene are associated with autosomal dominant CMT and with adult late onset SMA-like phenotype, further increasing the spectrum of clinical manifestations associated with MORC2 mutations.
15 Feb 2022Submitted to Human Mutation
15 Feb 2022Submission Checks Completed
15 Feb 2022Assigned to Editor
01 Mar 2022Reviewer(s) Assigned
10 May 2022Review(s) Completed, Editorial Evaluation Pending
11 May 2022Editorial Decision: Revise Minor
10 Jun 20221st Revision Received
10 Jun 2022Submission Checks Completed
10 Jun 2022Assigned to Editor
27 Jul 2022Review(s) Completed, Editorial Evaluation Pending
27 Jul 2022Editorial Decision: Accept