期刊
ENDOCRINOLOGY
卷 156, 期 1, 页码 377-388出版社
ENDOCRINE SOC
DOI: 10.1210/en.2014-1628
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资金
- Canadian Institutes of Health Research
- Fonds de Recherche du Quebec-Sante
- Heart and Stroke Foundation of Canada [GMHD79045]
- Girafonds/Fondation du Centre Hospitalier Universitaire Sainte-Justine
- European Society for Pediatric Endocrinology (ESPE Research Unit grant)
- Belgian Fonds de la Recherche Scientifique Medicale [FRSM 3_4598_12]
- Action de Recherche Concertee de la Communaute Francaise de Belgique [ARC AUWB-2012-12/17-ULB3]
- Fonds d'Encouragement a la Recherche
- Belgian National Fund for Scientific Research (FNRS)
Congenital hypothyroidism caused by thyroid dysgenesis (CHTD) is a common congenital disorder with a birth prevalence of 1 case in 4000 live births, and up to 8% of individuals with CHTD have co-occurring congenital heart disease. Initially we found nine patients with cardiac and thyroid congenital disorders in our cohort of 158 CHTD patients. To enrich for a rare phenotype likely to be genetically simpler, we selected three patients with a ventricular septal defect for molecular studies. Then, to assess whether rare de novo copy number variants and coding mutations in candidate genes are a source of genetic susceptibility, we used a genome-wide single-nucleotide polymorphism array and Sanger sequencing to analyze blood DNA samples from selected patients with co-occurring CHTDa congenital heart disease. We found rare variants in all three patients, and we selected Netrin-1 as the biologically most plausible contributory factor for functional studies. In zebrafish, ntn1a and ntn1b were not expressed in thyroid tissue, but ntn1a was expressed in pharyngeal arch mesenchyme, and ntn1a-deficient embryos displayed defective aortic arch artery formation and abnormal thyroid morphogenesis. The functional activity of the thyroid in ntn1a-deficient larvae was, however, preserved. Phenotypic analysis of affected zebrafish indicates that abnormal thyroid morphogenesis resulted from a lack of proper guidance exerted by the dysplastic vasculature of ntn1a-deficient embryos. Hence, careful phenotyping of patients combined with molecular and functional studies in zebrafish identify Netrin-1 as a potential shared genetic factor for cardiac and thyroid congenital defects.
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