Perspectives and Open Questions

Often in science, the answer to a question germinates a myriad of new questions. After its cloning, an enormous amount of work was devoted to define the physiological role of pendrin in the different organs in which it is expressed, and to understand the precise cellular events leading to disease following alteration of pendrin function by genetic mutation. In this scenario, several aspects still remain to be fully elucidated. For example, the striking intrafamilial variability in terms of deafness and goiter phenotype in Pendred syndrome has always intrigued scientists: What other factors, besides pendrin mutations, contribute to the severity of the disease? Why are some individuals with biallelic pendrin mutations affected by nonsyndromic deafness (DFNB4), while others develop the full spectrum of symptoms typical of Pendred syndrome? What are the precise molecular and cellular events culminating to inner ear malformations and deafness following alteration of pendrin activity?

Also, the precise functional role of pendrin in the thyroid is still a matter of debate. Is pendrin the true apical iodide transporter of the thyrocyte, responsible for the iodide flux into the follicular lumen, or does it rather control the cytosolic and/ or follicular pH by acting as a transporter of bicarbonate? If pendrin is the apical iodide transporter of the thyrocyte, why do mice models lacking pendrin expression not develop goiter? On the other hand, if pendrin is not the apical iodide transporter, why do patients with Pendred syndrome develop thyroid dysfunction and goiter?

Besides being expressed in the inner ear and thyroid, pendrin is also found in the kidneys, airways, and several other tissues, although the expression levels are lower compared to those of the thyroid. Although kidney and lung diseases are not manifested in Pendred syndrome, emerging evidence points to an important role of pendrin in controlling the acid-base status of the organism, blood pressure, and airway surface liquid volume.

Therefore, pendrin seems to be an attractive drug target, and it remains to be seen whether or not the transporter can be effectively and safely targeted in the treatment of hearing loss, hypertensive states, or airway distresses.

Box 1.1

The original article of V. Pendred, describing the disorder which came to be known as Pendred syndrome. Taken from Pendred (1896), with permission.

Clinical Notes:

Medical, Surgical, Obstetrical, and Therapeutical.

Deaf-Mutism and Goitre.

By Vaughan Pendred, M.R.C.S. Eng., L.R.C.P. Lond., Late house surgeon Guy’s Hospital

The curious association of deaf-mutism and goiter occurring in two members of a large family has induced me to record these cases. Why this association? Perhaps, some readers of THE LANCET may be able to throw some light on the causes of this combination of diseases: Absence of thyroid-cretinism; overgrowth of thyroid-deaf-mutism. I append the family history as recounted to me by the mother. The family is an Irish one, and the parents have been upwards of 40 years resident in Durham. The father, aged 66 years, and the mother, aged 67 years, are alive and healthy. They have had ten children, five sons, and five daughters. In an episode of smallpox 25 years ago, the whole family was attacked with the exception of the younger of the deaf-mutes, and four males and one female died, although all had been vaccinated, and this recently, as they were children. The remaining son and two of the daughters are healthy and vigorous. The first goiter case is the first-born of the family - a spare woman now aged 38 years. She is deaf and can only mumble indistinctly; little care has been taken to educate her and so she is imbecile. The goiter is a large multilobular hard tumor, the greater part on the right side of the neck; from time to time, she suffers from dyspneic attacks. The growth was first observed after the smallpox, i.e., at 13 years of age. The second surviving girl is now aged 28 years and is the fifth of the family; she is a small, spare, intelligent woman, her expression being in marked contrast to her sister’s. She is not absolutely deaf and can mumble incoherently; her education has been attended to with so much success that she has been “in service.” The tumor is larger than in the other case, but is of the same character; it has been growing for about 15 years, and during the last year has caused both dyspnea and dysphagia, which have become so urgent that I have sent her today to Newcastle Infirmary for operation.

Durham.

 
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