Investigating the structural impacts of a novel missense variant identified with whole exome sequencing in an Egyptian patient with propionic acidemia

Abstract

Propionic Acidemia (PA) is an inborn error of metabolism caused by variants in the PCCA or PCCB genes, leading to mitochondrial accumulation of propionyl-CoA and its by-products. Here, we report a 2 year-old Egyptian boy with PA who was born to consanguineous parents. Biochemical analysis was performed using tandem mass spectrometry (MS/MS) on the patient's dried blood spots (DBS) followed by urine examination of amino acids using gas chromatography/mass spectrometry (GC/MS). Molecular genetic analysis was carried out using whole-exome sequencing (WES). The PCCA gene sequencing revealed a novel homozygous missense variant affecting the locus (chr13:100962160) of exon 16 of the PCCA gene, resulting in the substitution of the amino acid arginine with proline at site 476 (p.Arg476Pro). Computational analysis revealed that the novel variant might be pathogenic and attributed to decrease the stability and also has an effect on the biotin carboxylase c-terminal domain of the propionyl carboxylase enzyme. The physicochemical properties analysis using NCBI amino acid explorer study revealed restrictions in the side chain and loss of hydrogen bonds due to the variant. On the structural level, the loss of beta-sheet was observed due to the variant proline, which has further led to the loss of surrounding interactions. This loss of beta-sheet and the surrounding interactions might serve the purpose of the structural stability changes. The current study demonstrates that a combination of whole-exome sequencing (WES) and computational analysis are potent tools for validation of diagnosis and classification of disease-causing variants.

Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis

“…Both genes are linked to inflammation, a process in which multiple pathways interact to contribute to this complex function. The LILRB1 gene is a member of the leukocyte immunoglobulin-like receptor (LILRs; or ILT, LIR, and CD85) family, which are the most conserved genes located within the leukocyte receptor cluster on human chromosome 19 (35,36). The family consists of 13 members with activating or inhibitory properties: LILRs with long cytoplasmic tails that contain inhibitory motifs based on tyrosine act as inhibitory receptors (LILRBs), whereas LILRs with short cytoplasmic tails act as activators (LILRAs).…”

Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects

“…The amino acid residue level structural deviation observed with the variant serine (Pro765Ser) in MYO1D is likely to disturb the primary, secondary, tertiary, and quaternary structural features in the protein. Numerous studies have shown the strong correlation between deviations in residue level RMSD score and structural properties for the disease-causing variants (23,(57)(58)(59). Disease causative pathogenic mutations have often changed the energy equilibrium, which is required to maintain the protein stability (60).…”

The genetics of mitochondrial disease: dissecting mitochondrial pathology using multi‐omic pipelines

“…Tandem mass spectrometry (MS/MS) was performed on the patient's dried blood spots, revealing an elevated C3‐carnitine and C3‐/C2‐carnitine ratio, whilst urinary amino acids were evaluated using gas chromatography/mass spectrometry (GC/MS), which demonstrated increased excretion of methyl citrate and 3‐hydroxy‐propionate. The patient's metabolomic profiles, together with in silico modelling of the c.1427G>C p.(Arg476Pro) PCCA variant, facilitated its classification as ‘likely pathogenic’, thereby confirming the diagnosis [ 97 ].…”