Molecular modelling
In many publications, it has been reported that M-D has been linked to
all types of variants including single-exonic deletions, interstitial
deletions, indels, in-frame deletions, non-synonymous single-nucleotide
missense, splice and the vast majority of indels lead to frameshifts and
stops. Le Doux, (2020) has compiled all variants reported and ranked
them by scores of deleteriousness, within the gnomAD v2 dataset. The new
mutation has not been reported before but the same position has been
found c.662G> A causing protein change Gly to Asp (Pell et
al., 2014). To understand the effect of the new mutation, a molecular
modelling has been conducted. The p.Gly221Val substitution was predicted
to be damaging according to six bioinformatics programs including
Polyphen, SIFT, Proven, Condel, Mutation Assessor and Mutation
Taster (Table 1 ). This mutation was not found in Exome Variant
Server (EVS) and Exome Aggregation Consortium (ExAC) databases.
Moreover, multi-sequence alignment of the human SGCE protein and its
orthologous proteins showed a highly conservation of the Gly221 amino
acid among species (Figure 3.A and B ).
A 3D structure of SGCE protein was built to explore the structural
impact of the p.Gly221Val mutation. The amino acid interaction analysis
has revealed that this missense mutation may disrupt hydrophobic
interactions between the amino acid in position 221 and its adjacent
residues. The mutated structure lacks one hydrophobic interaction
compared to the native structure. The hydrophobic interactions with
Lys167 and Tyr223 residues were conserved in the mutated protein,
whereas interactions with Ala204, Glu220, Asn168 and Val222 was replaced
by interactions with Gly209, Lys219 and Met169 (Figure 4 ). In
addition, this substitution is likely to decrease the SGCE protein
stability according to the predictions of CUPSAT, mCSM, SDM, DUET and
DeepDDG programs (Table 2 ).
This missense mutation is added to other six missense variants reported
in (Le Doux.2020) which the CADD_ PHRED scores range from 23.8 to 35
and are predicted to cause disease by MetaLR, MetaSVM, and
MutationTaster. REVEL_rankscores ranged from 0.852 (p.Thr36Arg) to
0.997 (p.Tyr115Cys). SGCE variants predicted to be deleterious by
in silico analysis may appear in patients undergoing whole-exome or
whole-genome sequencing for seemingly unrelated disorders. it has been
estimated that approximately 1/348 individuals in the United States
population host a SGCE variant with a CADD score ≥ 25 (LeDoux,
2020). This is suggesting that M-D and minor phenotypic variants such as
mild isolated myoclonus may be underdiagnosed.