Galactosemia, a single gene disorder with epigenetic consequences.

Hdl Handle:
http://hdl.handle.net/10147/267654
Title:
Galactosemia, a single gene disorder with epigenetic consequences.
Authors:
Coman, David J; Murray, David W; Byrne, Jennifer C; Rudd, Pauline M; Bagaglia, Paola M; Doran, Peter D; Treacy, Eileen P
Affiliation:
National Centre for Inherited Metabolic Disorders, Children's University Hospital, Dublin 1, Ireland.
Citation:
Galactosemia, a single gene disorder with epigenetic consequences. 2010, 67 (3):286-92 Pediatr. Res.
Journal:
Pediatric research
Issue Date:
Mar-2010
URI:
http://hdl.handle.net/10147/267654
DOI:
10.1203/PDR.0b013e3181cbd542
PubMed ID:
19952866
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed/19952866
Abstract:
Long-term outcomes of classic galactosemia (GAL) remain disappointing. It is unclear if the complications result mainly from prenatal-neonatal toxicity or persistent glycoprotein and glycolipid synthesis abnormalities. We performed gene expression profiling (T transcriptome) to characterize key-altered genes and gene clusters of four patients with GAL with variable outcomes maintained on a galactose-restricted diet, compared with controls. Significant perturbations of multiple cell signaling pathways were observed including mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton, focal adhesion, and ubiquitin mediated proteolysis. A number of genes significantly altered were further investigated in the GAL cohort including SPARC (osteonectin) and S100A8 (S100 calcium-binding protein). The whole serum N-glycan profile and IgG glycosylation status of 10 treated patients with GAL were compared with healthy control serum and IgG using a quantitative high-throughput analytical HPLC platform. Increased levels of agalactosylated and monogalactosylated structures and decreases in certain digalactosylated structures were identified in the patients. The persistent abnormal glycosylation of serum glycoproteins seen with the microarray data indicates persisting metabolic dyshomeostasis and gene dysregulation in "treated" GAL. Strict restriction of dietary galactose is clearly life saving in the neonatal period; long-term severe galactose restriction may contribute to ongoing systemic abnormalities.
Language:
en
MeSH:
Adult; Biological Markers; Child, Preschool; Chromatography, High Pressure Liquid; Epigenesis, Genetic; Female; Galactosemias; Gene Expression Profiling; Glycoproteins; Glycosylation; Humans; Immunoglobulin G; Male; Oligonucleotide Array Sequence Analysis; Polysaccharides; Protein Processing, Post-Translational; Signal Transduction
ISSN:
1530-0447

Full metadata record

DC FieldValue Language
dc.contributor.authorComan, David Jen_GB
dc.contributor.authorMurray, David Wen_GB
dc.contributor.authorByrne, Jennifer Cen_GB
dc.contributor.authorRudd, Pauline Men_GB
dc.contributor.authorBagaglia, Paola Men_GB
dc.contributor.authorDoran, Peter Den_GB
dc.contributor.authorTreacy, Eileen Pen_GB
dc.date.accessioned2013-01-30T10:19:19Z-
dc.date.available2013-01-30T10:19:19Z-
dc.date.issued2010-03-
dc.identifier.citationGalactosemia, a single gene disorder with epigenetic consequences. 2010, 67 (3):286-92 Pediatr. Res.en_GB
dc.identifier.issn1530-0447-
dc.identifier.pmid19952866-
dc.identifier.doi10.1203/PDR.0b013e3181cbd542-
dc.identifier.urihttp://hdl.handle.net/10147/267654-
dc.description.abstractLong-term outcomes of classic galactosemia (GAL) remain disappointing. It is unclear if the complications result mainly from prenatal-neonatal toxicity or persistent glycoprotein and glycolipid synthesis abnormalities. We performed gene expression profiling (T transcriptome) to characterize key-altered genes and gene clusters of four patients with GAL with variable outcomes maintained on a galactose-restricted diet, compared with controls. Significant perturbations of multiple cell signaling pathways were observed including mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton, focal adhesion, and ubiquitin mediated proteolysis. A number of genes significantly altered were further investigated in the GAL cohort including SPARC (osteonectin) and S100A8 (S100 calcium-binding protein). The whole serum N-glycan profile and IgG glycosylation status of 10 treated patients with GAL were compared with healthy control serum and IgG using a quantitative high-throughput analytical HPLC platform. Increased levels of agalactosylated and monogalactosylated structures and decreases in certain digalactosylated structures were identified in the patients. The persistent abnormal glycosylation of serum glycoproteins seen with the microarray data indicates persisting metabolic dyshomeostasis and gene dysregulation in "treated" GAL. Strict restriction of dietary galactose is clearly life saving in the neonatal period; long-term severe galactose restriction may contribute to ongoing systemic abnormalities.en_GB
dc.language.isoenen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/19952866en_GB
dc.rightsArchived with thanks to Pediatric researchen_GB
dc.subject.meshAdult-
dc.subject.meshBiological Markers-
dc.subject.meshChild, Preschool-
dc.subject.meshChromatography, High Pressure Liquid-
dc.subject.meshEpigenesis, Genetic-
dc.subject.meshFemale-
dc.subject.meshGalactosemias-
dc.subject.meshGene Expression Profiling-
dc.subject.meshGlycoproteins-
dc.subject.meshGlycosylation-
dc.subject.meshHumans-
dc.subject.meshImmunoglobulin G-
dc.subject.meshMale-
dc.subject.meshOligonucleotide Array Sequence Analysis-
dc.subject.meshPolysaccharides-
dc.subject.meshProtein Processing, Post-Translational-
dc.subject.meshSignal Transduction-
dc.titleGalactosemia, a single gene disorder with epigenetic consequences.en_GB
dc.contributor.departmentNational Centre for Inherited Metabolic Disorders, Children's University Hospital, Dublin 1, Ireland.en_GB
dc.identifier.journalPediatric researchen_GB
dc.description.provinceLeinsteren

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