Colhoun, Hugh Owen and Gozalbo, Estela M. Rubio and Bosch, Annet M and Knerr, Ina and Dawson, Charlotte and Brady, Jennifer and Galligan, Marie and Stepien, Karolina M and O'Flaherty, Roisin and Moss, C. Catherine and Barker, P. Peter and Fitzgibbon, Maria and Doran, Peter P. and Treacy, Eileen P. (2018) Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions. Orphanet Journal of Rare Diseases, 13 (164). pp. 1-13. ISSN 1750-1172

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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.

Item Type:	Article
Keywords:	Classical galactosaemia; Infertility; Glycan modifier genes;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	15049
Identification Number:	https://doi.org/10.1186/s13023-018-0906-3
Depositing User:	Roisin O'Flaherty
Date Deposited:	22 Nov 2021 15:22
Journal or Publication Title:	Orphanet Journal of Rare Diseases
Publisher:	BMC
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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