A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft...

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• Thyroid dysgenesis is a primary cause of congenital hypothyroidism (CH), with its genetic underpinnings largely unidentified.
• The transcription factor TTF-2 (FOXE1) plays a crucial role in thyroid development.

Purpose of the Study:

• To investigate the genetic basis of CH in siblings presenting with athyreosis and cleft palate.
• To characterize a novel mutation in the TTF-2 gene and its functional consequences.

Main Methods:

• Genetic sequencing to identify mutations in the TTF-2 gene.
• Analysis of TTF-2 protein function, including DNA binding and transcriptional activity.
• Clinical evaluation of affected individuals and their family members.

Main Results:

• Two male siblings with CH, athyreosis, and cleft palate were found to be homozygous for a novel TTF-2 mutation (S57N).
• The S57N mutation in the forkhead DNA binding domain resulted in impaired DNA binding and reduced transcriptional function of TTF-2.
• The identified mutation was absent in unaffected parents and controls, supporting its pathogenic role.

Conclusions:

• This study identifies a second homozygous missense mutation in TTF-2 associated with syndromic congenital hypothyroidism.
• The findings underscore the critical role of TTF-2 in both thyroid and palate development.
• Phenotypic variability in CH associated with TTF-2 mutations suggests complex genotype-phenotype correlations.