Novel variants in PCCA and PCCB Genes in Chinese Patients with propionic acidemia
Description
Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by the deficiency of the mitochondrial protein propionyl-CoA carboxylase (PCC) and associated with pathogenic variants in either of the two genes, PCCA or PCCB. In the present study, three PA patients were diagnosed by using gas chromatography-mass spectrometry(GC-MS), tandem mass spectrometry (MS/MS) and Molecular diagnostic methods. All patients had onset in neonatal period. One patient died of infection and metabolic decompensation, and the other two had mild to moderate developmental delay/mental retardation. Mutation analysis of the PCCA gene identified compound heterozygous c.1288C>T(p.R430X) and c.2002G>A(p.G668R) in patient 1, homozygous c.1426C>T(p.R476X) in patient 2; mutation analysis of the PCCB gene identified compound heterozygousc.359_360del AT(p.Y120Cfs*40) and c.1398+1G>A in patient 3. Three novel mutations (c.1288C>T, c.359_360del AT and c.1398+1G>A were identified in PCCA and PCCB genes. Among them, in the PCCA gene, c.1288C>T(p.R430X) was a nonsense mutation, resulting in a truncated protein. c.359_360del AT was a frameshift mutation, leading to p.Y120Cfs*40 mutation of amino acid sequence in PCCB. c.1398+1G>A was a splicing mutation, causing skipping of the exons 13-14. In conclusion, the novel mutations of this study will expands the mutation spectrum of PA.
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The three unrelated patientswere clinically diagnosed with PA using via urine organic acid analysis by gas chromatography-mass spectrometry (GC-MS) and carnitine analysis by tandem mass spectrometry (MS/MS). Genomic DNA of all affected individuals was subjected to Sanger sequencing, and candidate mutations were verified by Sanger sequencing in all available family members.