EDITORIAL FOCUS
An ion transporter involved in congenital deafness Focus on
"Human pendrin expressed in Xenopus laevis oocytes
mediates chloride/formate exchange"
John
Cuppoletti
Department of Molecular and Cellular Physiology, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0576
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ARTICLE |
CONGENITAL HEARING IMPAIRMENT is inherited in about
one-half of all cases. Of the 1 in 2,000 annual births so affected
(11), a large proportion (>1 in 10,000) (2, 4, 12) have defects in
the anion transport protein, pendrin. Clinical findings include progressive hearing loss, displasia of the cochlea, a widened vestibular aqueduct (2), and sometimes thyroid problems (19), including
goiter (Pendred syndrome) (14).
The disease is caused by several different mutations in pendrin (2, 5,
12, 15). Pendrin is an 86-kDa protein (4) that maps to human chromosome
7 (1, 4, 19). Pendrin mRNA has been localized to several cell types of
the inner ear (5), which may be involved in resorption of endolymphatic
fluid (20). Endolymphatic fluid is rich in K+ and has a
highly positive potential relative to the plasma (20). Pendrin mRNA
levels are highest in the thyroid (4) and may be localized to the
follicular cells (5). Lower levels of pendrin mRNA are also found in
the fetal kidney and fetal brain (4).
Pendrin has structural similarity to a variety of transport proteins
(4), including sulfate transporters and the more closely related DRA
(downregulated in adenoma) (16) and DTD (diastrophic dysplasia)
proteins (7).
Direct measurement of transport properties of the recombinant protein
in Xenopus oocytes showed that pendrin transported halides, including iodide, but not sulfate (18). Iodide transport by pendrin is
consistent with thyroid disease in Pendred syndrome.
In the current article in focus, Scott and Karniski (Ref. 17, see page
C207 in this issue) further explore the anion transport properties of pendrin. They now show that pendrin mediates the transport of formate (chloride/formate exchange). The
Km for chloride and inhibitor sensitivity (18) are
similar to the properties of the renal chloride/formate exchanger (9),
but it is not known whether renal chloride/formate exchange activity is
due to pendrin. Kidney disease has not been found to be associated with
mutations in pendrin, but loss of chloride/formate exchange (or other
anion transport activity of pendrin) in the inner ear could be a direct
or indirect cause of the structural changes such as dilation of the
vestibular aqueduct and other cochlear defects (2).
The findings of this article are an important part of a large and
successful effort to understand the genetic and functional basis of
congenital hearing impairment (see "Online Mendelian Inheritance in
Man" http://www3.ncbi.nlm.nih.gov/Omim). An important goal of these
studies is to understand how these proteins participate in normal
physiological processes and how mutations lead to disease. This article
helps to demonstrate that functional studies are absolutely essential
to confirm and extend predictions made from computational analysis
("bioinformatics"). Substrate specificity, turnover numbers,
regulatory properties, stoichiometry, electrogenicity, to name a few
functional properties, are defined by appropriate functional
measurements. Comparing and contrasting the wild-type and mutant
proteins to determine how the mutations affect the above properties and
other properties such as cellular trafficking, degradation, and ion
gradients is now possible and required for further progress.
Deafness and loss of inner ear structure is also a common finding in
mouse models where a variety of other transport genes, including the
Na+-K+-2Cl
cotransporter (3, 6),
the Ca2+-ATPase (10), a K+ channel (13), and
the H+-ATPase (8), have been ablated or mutated. These
models demonstrate that ion transport processes play important yet
poorly understood roles in developmental processes that are involved in
creation and maintenance of anatomic structures in the ear and elsewhere.
Elucidation of the role of anion transport by pendrin in the gross
anatomic changes in the inner ear and thyroid will be an important next
step in understanding congenital hearing impairment and perhaps
providing therapies.
Lessons learned from these studies may also lead to the further
understanding of other diseases such as cystic fibrosis, where mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in complex changes in epithelial cell function and, ultimately, morbidity and death, which are not easily related to the
chloride channel functions of CFTR alone.
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