A novel PCCB mutation in a Thai patient with propionic acidemia identified by exome sequencing.
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ABSTRACT:
SUBMITTER: Porntaveetus T
PROVIDER: S-EPMC4785532 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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A novel PCCB mutation in a Thai patient with propionic acidemia identified by exome sequencing.
Porntaveetus Thantrira T Srichomthong Chalurmpon C Suphapeetiporn Kanya K Shotelersuk Vorasuk V
Human genome variation 20150917
Propionic acidemia (PA) is an inborn error of metabolism, caused by mutations in either the PCCA or PCCB gene, leading to mitochondrial accumulation of propionyl-CoA and its by-products. Here we report a 6-year-old Thai boy with PA who was born to consanguineous parents. Exome sequencing identified a novel homozygous frameshift insertion (c.379_380insA; p.T127NfsX160) in the PCCB gene, expanding its mutational spectrum. ...[more]
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Project description: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.
| S-EPMC7502849 | biostudies-literature
Project description:Background: Propionic acidemia (PA) is an extremely rare autosomal recessive disorder which is caused by the deficiency of propionyl-CoA carboxylase (PCC) and associated with pathogenic variants in PCCA or PCCB gene. Case Report: Detection of PA in neonates is possible using Propionyl carnitine (C3) analysis by tandem mass spectrometry (MS/MS) in dried blood spots (DBS). Here we report one patient with PA. C3 in this case was normal in the initial screening and recall check and only manifested as the slightly increase of C3/C2, 3-hydroxypropionate in urine was only slightly elevated. Then two pathogenic mutations (c.802C>T/c.827delG) were detected in the PCCA gene by Genetic diagnosis panel. Among them, the variation rs774738181 (c.802C>T) was present on the dbSNP database which appeared to be "Likely pathogenic" in GenBank dbSNP (100915068). c.827delG was a novel frameshift mutation, leading to p.Gly276ValfsX46 mutation of amino acid sequence in PCCA. The patient underwent 1 year of follow-up, had total of 7 times and remain asymptomatic whose blood ammonia and liver function were normal. When the child was 1 year of age (in May of 2017), C3 and 3-Hydroxypropionate sudden elevated significantly, that proved pathogenicity of c.802C>T and c.827delG. Conclusion: Two novel mutations (c. 802C>T and c.827delG) in PCCA gene may be associated with late-onset PA, expanding its mutational spectrum. Maybe there is relation between the severity of propionyl-CoA carboxylase (PCC) activity defects and different genotypes.
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