ZFIN ID: ZDB-PUB-141030-1
Functional Zebrafish Studies Based on Human Genotyping Point to Netrin-1 as a Link Between Aberrant Cardiovascular Development and Thyroid Dysgenesis
Opitz, R., Hitz, M.P., Vandernoot, I., Trubiroha, A., Abu-Khudir, R., Samuels, M., Désilets, V., Costagliola, S., Andelfinger, G., Deladoëy, J.
Date: 2015
Source: Endocrinology   1(1): 377-88 (Journal)
Registered Authors: Costagliola, Sabine, Opitz, Robert, Trubiroha, Achim, Vandernoot, Isabelle
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cardiovascular Abnormalities/genetics*
  • Female
  • Gene Expression Regulation, Developmental/physiology*
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease
  • Genotype*
  • Humans
  • Male
  • Morpholinos
  • Nerve Growth Factors/genetics
  • Nerve Growth Factors/metabolism*
  • Polymorphism, Single Nucleotide
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Synaptotagmins/genetics
  • Synaptotagmins/metabolism
  • Thyroid Dysgenesis/genetics*
  • Tumor Suppressor Proteins/genetics
  • Tumor Suppressor Proteins/metabolism*
PubMed: 25353184 Full text @ Endocrinology
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 CHTD a 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.