Pendred syndrome is an autosomal recessive disorder that is classically defined by the combination of sensorineural
deafness/
hearing impairment,
goiter, and an abnormal organification of
iodide with or without
hypothyroidism. The hallmark of the syndrome is the impaired hearing, which is associated with inner ear malformations such as an
enlarged vestibular aqueduct (EVA). The thyroid phenotype is variable and may be modified by the nutritional
iodine intake.
Pendred syndrome is caused by biallelic mutations in the SLC26A4/PDS gene, which encodes the multifunctional
anion exchanger pendrin. Pendrin has affinity for
chloride,
iodide, and
bicarbonate, among other
anions. In the inner ear, pendrin functions as a
chloride/bicarbonate exchanger that is essential for maintaining the composition and the potential of the endolymph. In the thyroid, pendrin is expressed at the apical membrane of thyroid cells facing the follicular lumen. Functional studies have demonstrated that pendrin can mediate
iodide efflux in heterologous cells. This, together with the thyroid phenotype observed in humans (
goiter, impaired
iodine organification) suggests that pendrin could be involved in
iodide efflux into the lumen, one of the steps required for
thyroid hormone synthesis.
Iodide efflux can, however, also occur in the absence of pendrin suggesting that other exchangers or channels are involved. It has been suggested that
Anoctamin 1 (ANO1/TMEM16A), a
calcium-activated
anion channel, which is also expressed at the apical membrane of thyrocytes, could participate in mediating apical efflux. In the kidney, pendrin is involved in
bicarbonate secretion and
chloride reabsorption. While there is no renal phenotype under basal conditions, severe metabolic
alkalosis has been reported in
Pendred syndrome patients exposed to an increased
alkali load. This review provides an overview on the clinical spectrum of
Pendred syndrome, the functional data on pendrin with a focus on its potential role in the thyroid, as well as the controversy surrounding the relative physiological roles of pendrin and
anoctamin.