Functional zebrafish studies based on human genotyping point to netrin-1 as a link between aberrant cardiovascular development and thyroid dysgenesis.

Abstract

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.

• Authors: Robert Opitz, Marc-Philip Hitz, Isabelle Vandernoot, Achim Trubiroha, Rasha Abu-Khudir, Mark Samuels, Valérie Désilets, Sabine Costagliola, Gregor Andelfinger, Johnny Deladoëy
• Journal: Endocrinology (Endocrinology) Vol. 156 Issue 1 Pg. 377-88 (Jan 2015) ISSN: 1945-7170 [Electronic] United States
• PMID: 25353184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Morpholinos
• NTN1 protein, human
• Nerve Growth Factors
• RNA, Messenger
• SYT17 protein, human
• Tumor Suppressor Proteins
• Zebrafish Proteins
• ntn1a protein, zebrafish
• Synaptotagmins
• Netrin-1

Topics

• 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, metabolism)
• Netrin-1
• Polymorphism, Single Nucleotide
• RNA, Messenger (genetics, metabolism)
• Synaptotagmins (genetics, metabolism)
• Thyroid Dysgenesis (genetics)
• Tumor Suppressor Proteins (genetics, metabolism)
• Zebrafish Proteins