Background:
Methylmalonic acidemia (MMA) is a rare metabolic disorder
resulting from functional defects in methylmalonyl-CoA mutase. Mutations
in the MMAB gene are responsible for the cblB type of vitamin
B12-responsive MMA.
Results:
This study used Whole-exome sequencing (WES), Sanger sequencing,
linkage analysis, and in-silico evaluation of the variants effect on
protein structure and function to confirm their pathogenicity in a
2-day-old neonate presenting an early-onset metabolic crisis and death.
WES revealed a homozygous missense variant on chromosome 12, the
NM_052845.4 (MMAB):c.557G > A, p.Arg186Gln, in exon 7, a highly
conserved and hot spot region for pathogenic variants. After being
confirmed by Sanger sequencing, the wild-type and mutant proteins
structure and function were modeled and examined using in-silico
bioinformatics tools and compared to the variant NM_052845.4
(MMAB):c.556C > T, p.Arg186Trp, a known pathogenic variant at the
same position. Comprehensive bioinformatics analysis showed a
significant reduction in the stability of variants and changes in
protein-protein and ligand-protein interactions. Interestingly, the
variant c.557G > A, p.Arg186Gln depicted more variations in the
secondary structure and less binding to the ATP and B12 ligands compared
to the c.556C > T, p.Arg186Trp, the known pathogenic variant.
Conclusion:
This study succeeded in expanding the variant spectra of the MMAB,
forasmuch as the variant c.557G > A, p.Arg186Gln is suggested as a
pathogenic variant and the cause of severe MMA and neonatal death. These
results benefit the prenatal diagnosis of MMA in the subsequent
pregnancies and carrier screening of the family members. Furthermore, as
an auxiliary technique, homology modeling and protein structure and
function evaluations could provide geneticists with a more accurate
interpretation of variants pathogenicity.
