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

Area of Science:

• Genetics
• Developmental Biology
• Endocrinology

Background:

• Congenital hypothyroidism (CH) with thyroid dysgenesis, cleft palate, and other features define Bamforth-Lazarus syndrome.
• Homozygous loss-of-function mutations in the FOXE1 gene are associated with this syndrome.

Observation:

• A novel homozygous FOXE1 missense mutation (p.R73S) was identified in a patient with athyreosis, cleft palate, and choanal atresia.
• This mutation was inherited from heterozygous, healthy parents.

Findings:

• In vitro studies demonstrated that the FOXE1-p.R73S mutation enhances the activity of thyroglobulin (TG) and thyroid peroxidase (TPO) gene promoters.
• This gain-of-function effect was confirmed by increased endogenous TG production in primary human thyrocytes.

Implications:

• The study identifies a novel mechanism for Bamforth-Lazarus syndrome, involving gene hyperactivity rather than loss-of-function.
• This expands the understanding of FOXE1's role in thyroid and palate development.