Baumgartner
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Stoffwechsel und Molekulare Pädiatrie, Abteilung für » Prof. Dr. Matthias R. Baumgartner » Baumgartner
Completed research project
| Title / Titel | THE MOLECULAR BASIS AND FUNCTIONAL CHARACTERIZATION OF HUMAN 3-METHYLCRTONYL-COA CARBOXYLASE DEFCIENCY | ||||||||
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| Abstract (PDF, 14 KB) | |||||||||
| Summary / Zusammenfassung | Isolated, biotin-resistant 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism that appears to be the most frequent organic aciduria detected in tandem mass spectrometry based neonatal screening programs. MCC is a heteromeric mitochondrial enzyme comprised of biotin-containing alpha subunits and smaller beta subunits. Our ongoing investigations on the molecular basis and functional characterization of human MCC deficiency have further increased the total number to 34 MCCA and 42 MCCB mutant alleles in a total of 110 patients with proven MCC deficiency. Our data demonstrate a lack of a clear correlation between genotype and phenotype, suggesting that factors other than the MCC loci must have a major influence on the phenotype of MCC deficiency. We have reported on the first case of MCC deficiency responsive to biotin which is explained by a dominant negative effect of the missense allele MCCA-R385S. In two patients with MCC deficiency we show that the absence of 3-MCG in urine raises the potential for misdiagnosis in the clinical chemistry laboratory based solely upon urine organic acid analysis. Finally, we demonstrate that the point mutation c.1054G>A in MCCB activates a cryptic exon by disrupting an exon splice enhancer thus providing a novel mechanism causing MCC deficiency. Our studies provide insight into the molecular biology of MCC and the molecular pathology of MCC deficiency. The proposed studies will help to establish practical guidelines for management of affected subjects. Furthermore, this work increases the understanding of the variables that contribute to the highly variable phenotypic expression of MCC deficiency and as such serves as a model for the complexity of monogenic traits. Finally, this work on MCC will serve as an example for other biotinylated enzymes and their disorders. |
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| Publications / Publikationen | Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D: The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Invest 107: 495-504, 2001Baumgartner MR, Dantas MF, Suormala T, Almashanu S, Giunta C, Friebel D, Gebhardt B, Fowler B, Hoffmann GF, Baumgartner ER, Valle D. Isolated 3-methylcrotonyl-CoA carboxylase deficiency: Evidence for an allele specific dominant negative effect and responsiveness to biotin therapy. Am J Hum Genet 75:790-800, 2004Dantas MF, Suormala T, Randolph A, Coelho D, Fowler B, Valle D, Baumgartner MR. 3-methylcrotonyl-CoA carboxylase deficiency: Mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening. Hum Mutat 26:164, 2005Baumgartner MR: Molecular mechanisms of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency. J Inher Metab Dis 28:301-309, 2005Wolfe LA, Fiegold DN, Vockley J, Walters N, Chambaz C, Suormala T, Koch HG, Matern D, Barshop BA, Cropcho LJ, §Baumgartner MR and §Gibson KM. Potential misdiagnosis of 3-methylcrotonyl-CoA carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine. Pediatrics 120:e1135 – e1340, 2007 § both last authors contributed equallyEminoglu FT, Ozcelik AA, Okur I, Tumer L, Biberoglu G, Demir E, Hasanoglu A, Baumgartner MR. 3-Methylcrotonyl-CoA carboxylase deficiency: phenotypic variability in a family. J Child Neurol. 24:478-81, 2009Stucki M, Suormala T, Fowler B, Valle D, Baumgartner MR. Cryptic exon activation by disruption of an exon splice enhancer: A novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency. J Biol Chem. 16;284(42):28953-7, 2009 | ||||||||
| Keywords / Suchbegriffe | 3-methylcrotonyl-CoA carboxylase, phenotypic variation, complementation, biotin, dominant negative mutation, complexity of monogenic traits | ||||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Others |
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| Duration of Project / Projektdauer | Jan 2002 to Dec 2011 |