New MORC2 gene mutations are associated with distinctive features: from
axonal neuropathy to late adult-onset spinal muscular atrophy like
phenotype
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.