A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome causing increased thyroidal gene expression.
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.


CONCLUSIONS
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.
1 Research Center for Growth and Signaling (INSERM U845), Université Paris Descartes , Sorbonne Paris Cité, Paris, France .
Aurore
A
Carré
Rasha T
RT
Hamza
Dulanjalee
D
Kariyawasam
Loïc
L
Guillot
Raphaël
R
Teissier
Elodie
E
Tron
Mireille
M
Castanet
Corinne
C
Dupuy
Mohamed
M
El Kholy
Michel
M
Polak
D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001324:Autoantigens / Q000235:genetics; D001483:Base Sequence; D002972:Cleft Palate / Q000235:genetics*; D004252:DNA Mutational Analysis; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015870:Gene Expression; D057809:HEK293 Cells; D006201:Hair Diseases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D007223:Infant; D007453:Iodide Peroxidase / Q000235:genetics; D033862:Iron-Binding Proteins / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D017386:Sequence Homology, Amino Acid; D013954:Thyroglobulin / Q000235:genetics; D050033:Thyroid Dysgenesis / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism; D014162:Transfection
D001324:Autoantigens; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D033862:Iron-Binding Proteins; D013954:Thyroglobulin; C056658:TPO protein, human; D007453:Iodide Peroxidase