Abstract
3-Methylcrotonylglycinuria is an organic aciduria resulting from deficiency of 3-methylcrotonyl-CoA carboxylase (3-MCC), a biotin-dependent mitochondrial enzym carboxylating 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA during leucine catabolism. Its deficiency, due to mutations on MCCC1 and MCCC2 genes, leads to accumulation of 3-methylcrotonyl-CoA metabolites in blood and/or urine, primarily 3-hydroxyisovaleryl-carnitine (C5-OH) in plasma and 3-methylcrotonyl-glycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA) in the urine. The phenotype of 3-MCC deficiency is highly variable, ranging from severe neurological abnormalities and death in infancy to asymptomatic adults. Here we report the biochemical and molecular characterization of an Italian asymptomatic girl, positive for the newborn screening test. Molecular analysis showed two mutations in the MCCC2 gene, an already described missense mutation, c.691A > T (p.I231F), and a novel splicing mutation, c.1150-1G > A. We characterized the expression profile of the splice mutation by functional studies.
Highlights
3-Methylcrotonylglycinuria (OMIM #210200, #210210) is an organic aciduria resulting from deficiency of 3-methylcrotonyl-CoA carboxylase (3-MCC, EC 6.4.1.4), a biotin-dependent mitochondrial enzyme involved in the fourth step of the catabolic pathway of the amino acid leucine (Sweetman and Williams, 2001) (Figure 1)
The 3-methylcrotonylglycinuria is the most frequent organic aciduria detected by an increase of C5-OH in tandem mass spectrometry-based newborn screening programs (NBS) (Gallardo et al, 2001)
Deficiency of 3-methylcrotonyl-CoA carboxylase does not show a good genotype-phenotype correlation, since deleterious mutations in homozygosis do not cause a clinical phenotype, and even complete absence of 3-MCC activity leads to clinical manifestations in a rather small subgroup of individuals (Dantas et al, 2005; Morscher et al, 2012)
Summary
3-Methylcrotonylglycinuria (OMIM #210200, #210210) is an organic aciduria resulting from deficiency of 3-methylcrotonyl-CoA carboxylase (3-MCC, EC 6.4.1.4), a biotin-dependent mitochondrial enzyme involved in the fourth step of the catabolic pathway of the amino acid leucine (Sweetman and Williams, 2001) (Figure 1). The clinical phenotype of 3-MCC deficiency is highly variable, ranging from severe neurological abnormalities and death in infancy (Baykal et al, 2005) to asymptomatic adults (Dantas et al, 2005; Forsyth et al, 2016). Most of the patients diagnosed by NBS as affected by 3-MCC deficiency appear to be asymptomatic during the whole life (Forsyth et al, 2016). In this report we present the biochemical and molecular characterization of an Italian girl, positive for the newborn screening test. We characterized the expression profile of the novel splice mutation by functional studies
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