Page 58 - Read Online

Page 342 Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04

HINT1
In 2012, the histidine triad nucleotide-binding protein 1 gene (HINT1) was identified in recessive forms of
axonal CMT (accounting for 10% of recessive CMT patients). At that time, it was reported that around 80%
of patients carrying HINT1-causative variants showed neuromyotonia . This phenotypic sign guided the
[92]
clinical diagnosis of these cases, and it was considered that HINT1-associated peripheral neuropathy
[93]
represented a distinct clinical and genetic entity that needed to be differentiated from other CMT types
described as axonal, motor-greater-than-sensory polyneuropathy with a childhood-onset, combined with
neuromyotonia [92,94-96] . However, the identification of more patients and/or causative mutations extended the
clinical spectrum. From the histological point of view, sural nerve biopsies of some reported cases showed
axonal neuropathy, even in the absence of clinical sensory abnormalities.

Interestingly, HINT1 has a non-random geographic distribution of patients. The majority of causative
[97]
mutations are found in Central and Eastern European individuals , and this has been attributed to three
different founder mutations, p.Arg37Pro, p.Cys84Arg, and p.His112Asn.

HINT1 encodes a member of the histidine triad (HIT) protein family. Specifically, it is a globular protein
that acts as a homodimer and binds purine nucleosides and nucleotides. Both its HIT motif and C-terminal
loop are essential to establishing nucleotide contacts and maintaining substrate specificity , respectively.
[98]
[98]
Furthermore, dimerization is required to maintain catalytic activity . Several studies have reported that
HINT1 mutations cause a loss-of-function effect through several mechanisms. For instance, they can affect
critical residues for catalytic activity, they can be related to nonsense mediated decay of mRNA, or they can
cause protein instability and, consequently, proteasome-mediated degradation .
[92]

MFN2
CMT type 2A is the most common axonal form of CMT and is caused almost exclusively by mutations in
the MFN2 gene . This type of CMT is characterized by peripheral neuropathy that can also involve the
[99]
[100]
central nervous system . Mutations in MFN2 usually have an autosomal dominant pattern of inheritance,
but, occasionally, MFN2 mutations can be recessive or even semidominant.

[101]
About 100 mutations in MFN2 related to CMT2A2 have been described , but the exact relationship
between the genotype and the phenotype of MFN2 patients remains to be clarified. Interestingly, a
childhood onset of autosomal dominant CMT2A2 is the most predictive marker of significant disease
severity . In general, in comparison to demyelinating CMT1A, axonal CMT2A2 is more severe and shows
[102]
a motor-predominant phenotype that usually carries a greater burden of disability [103,104] . MFN2 neuropathy
can also be associated with sensorineural hearing loss, optic atrophy, and, in some cases, cerebellar atrophy,
spastic paraparesis, and cognitive deficits.

Mitofusin-2 and -1 are homologous proteins, members of a mitochondrial transmembrane GTPase family.
They show ubiquitous expression in eukaryotic cells, where they play a role in the dynamic mitochondrial
remodeling process . Both of them are known to play a critical role in the mitigation of mitochondrial
[102]
stress, helping to maintain mitochondrial “quality control” and facilitate apoptosis if necessary (under
severe cellular stress) .
[105]

Mitofusin-2 has two main functions: the promotion of mitochondrial fusion and the mediation of
endoplasmatic reticulum (ER)-mitochondrial tethering at mitochondria-associated ER membranes
(MAMs) [106-108] . MAMs are essential to regulate key cellular functions regarding lipid and calcium
homeostasis [106,109-111] , as well as mitochondria dynamics and bioenergetics. In addition, it has been shown