NKX2-1

Brain-lung-thyroid syndrome

At least 100 mutations in the NKX2-1 gene have been found to cause brain-lung-thyroid syndrome, which encompasses a group of conditions that affect the brain, lungs, and thyroid gland. About half of affected individuals have problems with all three organs, while others have problems with one or two of them. The most common features of this syndrome are benign hereditary chorea, which involves involuntary jerking movements (chorea) of the face, torso, and limbs and other uncontrolled movements; severe breathing difficulty (respiratory distress syndrome); and reduced thyroid gland function (hypothyroidism).

Many of the NKX2-1 gene mutations involved in brain-lung-thyroid syndrome result in an abnormally short homeobox protein Nkx-2.1 that cannot function normally. Other mutations change single protein building blocks (amino acids) in the protein, impairing its ability to attach to DNA. Still others delete the whole NKX2-1 gene. A shortage of functional homeobox protein Nkx-2.1 alters the expression of genes important for the normal development and functioning of the brain, lungs, and thyroid. The production of surfactant proteins is reduced, leading to breathing difficulty; expression of genes involved in the production of thyroid hormones is impaired, accounting for hypothyroidism; and brain development is impaired, likely due to improper interneuron formation or migration, which may underlie the movement abnormalities characteristic of brain-lung-thyroid syndrome.