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 onMORC2 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 inMORC2 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.