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Open Access Research article

Circadian transcriptome analysis in human fibroblasts from Hunter syndrome and impact of iduronate-2-sulfatase treatment

Gianluigi Mazzoccoli1*, Rosella Tomanin2, Tommaso Mazza3, Francesca D’Avanzo2, Marika Salvalaio2, Laura Rigon2, Alessandra Zanetti2, Valerio Pazienza4, Massimo Francavilla5, Francesco Giuliani5, Manlio Vinciguerra6 and Maurizio Scarpa27

Author Affiliations

1 Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, S.Giovanni Rotondo (FG), Italy

2 Laboratory of Diagnosis and Therapy of Lysosomal Disorders, Department of Women’s and Children’s Health, University of Padova, Padova, Italy

3 Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, S.Giovanni Rotondo (FG), Italy

4 Research Laboratory of Gastroenterology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, S.Giovanni Rotondo (FG), Italy

5 Computing Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, S.Giovanni Rotondo (FG), Italy

6 Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK

7 Centre for Rare Disorders, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, S.Giovanni Rotondo (FG), Italy

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BMC Medical Genomics 2013, 6:37  doi:10.1186/1755-8794-6-37

Published: 2 October 2013

Abstract

Background

Hunter syndrome (HS) is a lysosomal storage disease caused by iduronate-2-sulfatase (IDS) deficiency and loss of ability to break down and recycle the glycosaminoglycans, heparan and dermatan sulfate, leading to impairment of cellular processes and cell death. Cell activities and functioning of intracellular organelles are controlled by the clock genes (CGs), driving the rhythmic expression of clock controlled genes (CCGs). We aimed to evaluate the expression of CGs and downstream CCGs in HS, before and after enzyme replacement treatment with IDS.

Methods

The expression levels of CGs and CCGs were evaluated by a whole transcriptome analysis through Next Generation Sequencing in normal primary human fibroblasts and fibroblasts of patients affected by HS before and 24 h/144 h after IDS treatment. The time related expression of CGs after synchronization by serum shock was also evaluated by qRT-PCR before and after 24 hours of IDS treatment.

Results

In HS fibroblasts we found altered expression of several CGs and CCGs, with dynamic changes 24 h and 144 h after IDS treatment. A semantic hypergraph-based analysis highlighted five gene clusters significantly associated to important biological processes or pathways, and five genes, AHR, HIF1A, CRY1, ITGA5 and EIF2B3, proven to be central players in these pathways. After synchronization by serum shock and 24 h treatment with IDS the expression of ARNTL2 at 10 h (p = 0.036), PER1 at 4 h (p = 0.019), PER2 at 10 h (p = 0.041) and 16 h (p = 0.043) changed in HS fibroblasts.

Conclusion

CG and CCG expression is altered in HS fibroblasts and IDS treatment determines dynamic modifications, suggesting a direct involvement of the CG machinery in the physiopathology of cellular derangements that characterize HS.

Keywords:
Clock gene; Hunter syndrome; Lysosomal storage disease; Circadian rhythm