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  Pyruvate carboxylase deficiency type A and type C: Characterization of 5 novel pathogenic variants in PC and analysis of the genotype-phenotype correlation.

Coci, E. G., Gapsys, V., Shur, N., Shin‐Podskarbi, Y., de Groot, B., Miller, K., et al. (2019). Pyruvate carboxylase deficiency type A and type C: Characterization of 5 novel pathogenic variants in PC and analysis of the genotype-phenotype correlation. Human Mutation, (in press). doi:10.1002/humu.23742.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-3282-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-3288-B
Genre: Journal Article

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 Creators:
Coci, E. G., Author
Gapsys, V.1, Author              
Shur, N., Author
Shin‐Podskarbi, Y., Author
de Groot, B.1, Author              
Miller, K., Author
Vockley, J., Author
Sondheimer, N., Author
Ganetzky, R., Author
Freisinger, P., Author
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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Free keywords: Biotin carboxyl carrier protein domain; Biotin carboxylase domain; Carboxyl transferase domain; Neuro-developmental delay; PC tetramerization domain; Pyruvate carboxylase; Pyruvate carboxylase deficiency
 Abstract: Pyruvate carboxylase deficiency (PCD) is caused by bi-allelic mutations of the PC gene. The reported clinical spectrum includes a neonatal form with early death (type B), an infantile fatal form (type A), and an late onset form with isolated mild intellectual delay (type C). Apart from homozygous stop-codon mutations leading to type B PCD, a genotype-phenotype correlation has not otherwise been discernible. Indeed, patients harboring bi-allelic heterozygous variants leading to PC activity near zero can present either with a fatal infantile type A or with a benign late onset type C form. In this study, we analyzed six novel patients with type A (three) and type C (three) PCD, and compared them with previously reported cases. Firstly, we observed that type C PCD is not associated to homozygous variants in PC. In-silico modeling was used to map former and novel variants associated to type A and C PCD, and to predict their potential effects on the enzyme structure and function. We found that variants lead to type A or type C phenotype based on the destabilization between the two major enzyme conformers. In general, our study on novel and previously reported patients improves the overall understanding on type A and C PCD.

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Language(s): eng - English
 Dates: 2019-03-14
 Publication Status: Published online
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 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1002/humu.23742
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Title: Human Mutation
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: (in press) Start / End Page: - Identifier: -