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Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.

Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.

Pubmed ID: 24530203 RIS Download

Mesh terms: Adolescent | Base Sequence | Carbonic Anhydrase V | Child | Child, Preschool | Exons | Female | Gene Deletion | Genetic Variation | Homozygote | Humans | Hyperammonemia | Infant | Liver | Male | Molecular Sequence Data | Mutation, Missense | Pedigree | Sequence Analysis, DNA | Temperature

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RefSeq

Database that provides a comprehensive, integrated, non-redundant, well-annotated set of sequences, including genomic DNA, transcripts, and proteins. It provides a stable reference for genome annotation, gene identification and characterization, mutation and polymorphism analysis (especially RefSeqGene records), expression studies, and comparative analyses. Included are sequences from plasmids, organelles, viruses, archaea, bacteria, and eukaryotes. Each RefSeq is constructed wholly from sequence data submitted to the International Nucleotide Sequence Database Collaboration (INSDC). It is a unique resource because it provides a large, multi-species, curated sequence database representing separate but explicitly linked records from genomes to transcripts and translation products, as appropriate. Unlike the sequence redundancy found in the public sequence repositories that comprise the INSDC, (i.e., NCBI's GenBank, the European Nucleotide Archive, and the DNA Data Bank of Japan), the RefSeq collection aims to provide, for each included species, a complete set of non-redundant, extensively cross-linked, and richly annotated nucleic acid and protein records. It is recognized, however, that the coverage and finishing of public sequence data varies from organism to organism so intermediate genomic records are provided in some circumstances. The RefSeq collection is available without restriction and can be retrieved in several different ways, such as by searching or by available links in NCBI resources, including PubMed, Nucleotide, Protein, Gene, and Map Viewer, searching with a sequence via BLAST, and downloading from the RefSeq FTP site.

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TIDE BC

A collaborative care and research initiative with a focus on prevention and treatment of Intellectual disability (ID) that is due to inborn errors of metabolism (IEM), which can be treated with diet or drugs. Health care policy and institutional culture is still operating under the old premise that all ID is incurable and thus, many children born with treatable ID are at risk of not being treated. To acknowledge the multidisciplinary scope and the ways in which health care professionals and researchers will collaborate, the goals of the TIDE BC project are demonstrated within a framework of 7 Work Packages: * Implementation of a new Protocol for diagnostic evaluation of ID, focusing of treatable conditions; * Development of infrastructure to facilitate implementation, evaluation and sustainability of the Protocol; * Investments into next generation genomic technologies; * Improving evidence of and access to treatments; * Evaluation and health economy; * Knowledge dissemination; * Education and Mentoring. The objectives addressed in all Work Packages reflect a highly integrated cluster combining clinical care, research, evaluation, and knowledge dissemination.

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NCBI BLAST

Web search tool to find regions of similarity between biological sequences. The program compares nucleotide or protein sequences to sequence databases and calculates the statistical significance.

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OMIM

Collection of human genes and genetic phenotypes, focusing on the relationship between phenotype and genotype. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and a variety of related genes. It is updated daily, and the entries contain copious links to other genetics resources.

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NHLBI Exome Sequencing Project (ESP)

The goal of the project is to discover novel genes and mechanisms contributing to heart, lung and blood disorders by pioneering the application of next-generation sequencing of the protein coding regions of the human genome across diverse, richly-phenotyped populations and to share these datasets and findings with the scientific community to extend and enrich the diagnosis, management and treatment of heart, lung and blood disorders. The groups participating and collaborating in the NHLBI GO ESP include: Seattle GO - University of Washington, Seattle, WA Broad GO - Broad Institute of MIT and Harvard, Cambridge, MA WHISP GO - Ohio State University Medical Center, Columbus, OH Lung GO - University of Washington, Seattle, WA WashU GO - Washington University, St. Louis, MO Heart GO - University of Virginia Health System, Charlottesville, VA ChargeS GO - University of Texas Health Sciences Center at Houston

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