A NovelFOXE1Mutation (R73S) in Bamforth–Lazarus Syndrome Causing Increased Thyroidal Gene Expression

Abstract

Background: Homozygous loss-of-function mutations in the FOXE1 gene have been reported in several patients with partial or complete Bamforth-Lazarus syndrome: congenital hypothyroidism (CH) with thyroid dysgenesis (usually athyreosis), cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. Here, our objective was to evaluate potential functional consequences of a FOXE1 mutation in a patient with a similar clinical phenotype. Methods: FOXE1 was sequenced in eight patients with thyroid dysgenesis and cleft palate. Transient transfection was performed in HEK293 cells using the thyroglobulin (TG) and thyroid peroxidase (TPO) promoters in luciferase reporter plasmids to assess the functional impact of the FOXE1 mutations. Primary human thyrocytes transfected with wild type and mutant FOXE1 served to assess the impact of the mutation on endogenous TG and TPO expression. Results: We identified and characterized the function of a new homozygous FOXE1 missense mutation (p.R73S) in a boy with a typical phenotype (athyreosis, cleft palate, and partial choanal atresia). This new mutation located within the forkhead domain was inherited from the heterozygous healthy consanguineous parents. In vitro functional studies in HEK293 cells showed that this mutant gene enhanced the activity of the TG and TPO gene promoters (1.5-fold and 1.7-fold respectively vs. wild type FOXE1; p < 0.05), unlike the five mutations previously reported in Bamforth-Lazarus syndrome. The gain-of-function effect of the FOXE1-p.R73S mutant gene was confirmed by an increase in endogenous TG production in primary human thyrocytes. Conclusion: We identified a new homozygous FOXE1 mutation responsible for enhanced expression of the TG and TPO genes in a boy whose phenotype is similar to that reported previously in patients with loss-of-function FOXE1 mutations. This finding further delineates the role for FOXE1 in both thyroid and palate development, and shows that enhanced gene activity should be considered among the mechanisms underlying Bamforth-Lazarus syndrome.

Development of the thyroid gland

“…Bamforth-Lazarus syndrome, which is caused by homozygous FOXE1 mutations, also reflects the embryonic expression of FOXE1 in affected tissues leading to, aside from thyroid dysgenesis, cleft palate, bifid epiglottis, choanal atresia and spiky hair (Clifton-Bligh et al, 1998). Interestingly, a consanguineously inherited gain-of-function mutation in FOXE1 reproduces athyreosis and craniofacial malformations (Carre et al, 2014), suggesting that FOXE1-mediated developmental regulation is critically dependent on gene dosage. It was also recently discovered that polymorphism within a FOXE1 non-coding enhancer element confers increased risk of developing CH, cleft palate and thyroid cancer (Lidral et al, 2015).…”

New insights into thyroid hormone action

“…Polymorphisms in NRG1 and FOXE1 were associated with a risk of follicular adenoma (Rogounovitch et al, 2015). Polymorphisms in FOXE1 are also associated with congenital hypothyroidism (Carre et al, 2014). Some polymorphisms have little to no effect in patient care such as the type 1 deiodinase (DIO1), which does not change the dose of T4 required for TSH suppression in thyroidectimized patients (Santoro et al, 2014).…”

TUBB 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

“…Abnormalities at any step of thyroid development may result in TD associated with hypothyroidism or not (Maiorana et al , ). Previous studies of sporadic and familial TD covering a wide clinical spectrum identified mutations in nine genes: PAX8 , NKX2‐1 , FOXE1 , NKX2‐5 , TSHR, GLIS3, NTN1 , JAG1 and BOREALIN (Dentice et al , ; Senée et al , ; Carré et al , , , ; Sura‐Trueba et al , ; Ramos et al , ; Opitz et al , ; de Filippis et al , ). However, mutations in these genes are found in only 5% of all patients with TD and identification of causative mutations remains a challenging task.…”