Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions
Abstract Background Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significa...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-09-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13023-018-0906-3 |
| _version_ | 1818340443062009856 |
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| author | Hugh-Owen Colhoun Estela M. Rubio Gozalbo Annet M. Bosch Ina Knerr Charlotte Dawson Jennifer Brady Marie Galligan Karolina Stepien Roisin O’Flaherty C. Catherine Moss P. Peter Barker Maria Fitzgibbon Peter P. Doran Eileen P. Treacy |
| author_facet | Hugh-Owen Colhoun Estela M. Rubio Gozalbo Annet M. Bosch Ina Knerr Charlotte Dawson Jennifer Brady Marie Galligan Karolina Stepien Roisin O’Flaherty C. Catherine Moss P. Peter Barker Maria Fitzgibbon Peter P. Doran Eileen P. Treacy |
| author_sort | Hugh-Owen Colhoun |
| collection | DOAJ |
| description | Abstract Background Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17–51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements. Results Twenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (rs = − 0.68) and (rs = − 0.94) respectively with lower circulating leptin in CG patients with reduced IgG galactosylation. In CG patients (males and females analysed as one group), the key glycan synthesis modifier genes MGAT3 and FUT8, which influence glycan chain bisecting and fucosylation and subsequent cell signalling and adhesion, were found to be significantly upregulated (p < 0.01 and p < 0.05) and also the glycan synthesis gene ALG9 (p < 0.01). Both leptin signalling genes LEP and LEPR were found to be upregulated (p < 0.01) as was the inflammatory genes ANXA1 and ICAM1 and the apoptosis gene SEPT4 (p < 0.01). Conclusions These results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI. |
| first_indexed | 2024-12-13T15:42:59Z |
| format | Article |
| id | doaj.art-8c25fe5bb1824dfc8bba90b86d1ba3af |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-13T15:42:59Z |
| publishDate | 2018-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-8c25fe5bb1824dfc8bba90b86d1ba3af2022-12-21T23:39:46ZengBMCOrphanet Journal of Rare Diseases1750-11722018-09-0113111310.1186/s13023-018-0906-3Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactionsHugh-Owen Colhoun0Estela M. Rubio Gozalbo1Annet M. Bosch2Ina Knerr3Charlotte Dawson4Jennifer Brady5Marie Galligan6Karolina Stepien7Roisin O’Flaherty8C. Catherine Moss9P. Peter Barker10Maria Fitzgibbon11Peter P. Doran12Eileen P. Treacy13Department of Paediatrics, Trinity CollegeDepartment of Pediatrics and Department of Clinical Genetics, Maastricht University Medical CentreDepartment of Pediatrics, Division of Metabolic Disorders, Academic Medical Center, University of AmsterdamNational Centre for Inherited Metabolic Disorders, Temple Street Children’s University Hospital and Mater Misericordiae University HospitalDepartment of Endocrinology, University Hospitals Birmingham NHS Foundation TrustDepartment of Clinical Biochemistry and Diagnostic Endocrinology, The Mater Misericordiae University HospitalUniversity College DublinMark Holland Metabolic Unit, Salford Royal NHS Foundation TrustNIBRT GlycoScience Group, National Institute for Bioprocessing, Research and TrainingCore Genomics Facility, Conway Institute, University CollegeCore Biochemical Assay Laboratory (CBAL), Clinical Biochemistry, Box 232, Cambridge University Hospitals NHS Foundation TrustDepartment of Clinical Biochemistry and Diagnostic Endocrinology, The Mater Misericordiae University HospitalUniversity College DublinDepartment of Paediatrics, Trinity CollegeAbstract Background Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17–51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements. Results Twenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (rs = − 0.68) and (rs = − 0.94) respectively with lower circulating leptin in CG patients with reduced IgG galactosylation. In CG patients (males and females analysed as one group), the key glycan synthesis modifier genes MGAT3 and FUT8, which influence glycan chain bisecting and fucosylation and subsequent cell signalling and adhesion, were found to be significantly upregulated (p < 0.01 and p < 0.05) and also the glycan synthesis gene ALG9 (p < 0.01). Both leptin signalling genes LEP and LEPR were found to be upregulated (p < 0.01) as was the inflammatory genes ANXA1 and ICAM1 and the apoptosis gene SEPT4 (p < 0.01). Conclusions These results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI.http://link.springer.com/article/10.1186/s13023-018-0906-3Classical galactosaemiaInfertilityGlycan modifier genes |
| spellingShingle | Hugh-Owen Colhoun Estela M. Rubio Gozalbo Annet M. Bosch Ina Knerr Charlotte Dawson Jennifer Brady Marie Galligan Karolina Stepien Roisin O’Flaherty C. Catherine Moss P. Peter Barker Maria Fitzgibbon Peter P. Doran Eileen P. Treacy Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions Orphanet Journal of Rare Diseases Classical galactosaemia Infertility Glycan modifier genes |
| title | Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions |
| title_full | Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions |
| title_fullStr | Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions |
| title_full_unstemmed | Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions |
| title_short | Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions |
| title_sort | fertility in classical galactosaemia a study of n glycan hormonal and inflammatory gene interactions |
| topic | Classical galactosaemia Infertility Glycan modifier genes |
| url | http://link.springer.com/article/10.1186/s13023-018-0906-3 |
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