Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 21, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn319
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Mutations in the SLC2A10 gene cause arterial abnormalities in mice
1 Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan
2 Molecular Medicine Program of Taiwan International Graduate Program, Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan, and Institute of Biochemistry, National Yang-Ming University, Taipei, 11221, Taiwan
3 Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA
* Corresponding author. Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 11529, Taiwan. Tel: 011-886-2-2789-9104; fax: 011-886-2-2782-5573. E-mail address: chen0010{at}ibms.sinica.edu.tw
Aims: Glucose transporter 10 (GLUT10), encoded by the SLC2A10 gene, is a member of the class III facilitative glucose transporter family. Mutations in the SLC2A10 gene cause arterial tortuosity syndrome (ATS) in humans. To further study the pathogenesis of the disease, we generated mice carrying GLUT10 mutations.
Methods and results: Using a gene-driven N-ethyl-N-nitrosourea (ENU)-mutagenesis approach we generated mice carrying GLUT10 mutations c.383G>A and c.449C>T, which resulted in missense mutations of glycine to glutamic acid (p.G128E) and serine to phenylalanine (p.S150F), respectively. Both mutant strains appeared normal at birth, gained weight appropriately and survived to adulthood (>18 months). Blood and urine glucose were normal. Echocardiogram and Electrocardiogram were also normal and brain magnetic resonance angiography revealed normal cerebral arteries without tortuosity, stenosis/dilatation or aneurysm. The histopathology revealed thickening and irregular vessel wall shape of large and medium size arteries characterized by markedly increased elastic fibers, both in number and size. There was also intima endothelial hypertrophy and deranged elastic fibers that resulted in disruption of internal elastic laminae in the aorta of older mice.
Conclusion: Abnormal elastogenesis with early elastic fiber proliferation provide a clue to the pathogenesis of arterial tortuosity in human ATS. Availability of this mouse model will allow testing of the relationship between diabetes and its vascular complications, including diabetic retinopathy, nephropathy and peripheral vascular disease.
Time for primary review: 16 Days