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Gillam, Kopp
Molecular analysis of the PDS gene in a nonconsanguineous Sicilian family with Pendred's syndrome.Gillam MP, Bartolone L, Kopp P, Bevenga S. Thyroid. 2005 Jul;15(7):734-41. [abstract only]
"OBJECTIVE: The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a chloride/iodide transporter expressed in the thyroid, the inner ear, and the kidney. In this study we performed clinical and molecular analyses in three siblings from a nonconsanguineous Sicilian family who presented with the clinical features of Pendred's syndrome.
PATIENTS AND MOLECULAR ANALYSES: In two sisters and one brother, the clinical diagnosis of Pendred's syndrome was established based on the findings of sensorineural hearing loss and large goiters. Thyroid function tests, perchlorate discharge tests, thyroid ultrasound, and scintigraphy were performed in all affected individuals. Exons 2 to 21 of the PDS gene were amplified by polymerase chain reaction (PCR) and both strands were submitted to direct sequence analysis.
RESULTS: The clinical diagnosis of Pendred's syndrome was supported by a positive perchlorate discharge test in the three afflicted siblings. Direct sequence analysis of the PDS gene revealed that all three harbored one allele with a novel mutation 890delC leading to a frameshift mutation and premature stop codon at position 302 (FS297 > 302X). On the other allele, two of the siblings had a previously described transition 1226G > A, which results in the substitution of arginine by histidine at position 409 (R409H). In the index patient, no mutation could be identified on the other allele. In functional studies, these mutants lose the ability of pendrin to mediate iodide efflux.
CONCLUSIONS: All three patients included in this
study presented with the classic Pendred syndrome triad. Two siblings
were compound heterozygous for mutations in the coding region of the
PDS gene. The third individual could have an unidentified mutation in
a regulatory or intronic region of the PDS gene, or an identical
phenotype caused by distinct pathogenic mechanisms."
Functional characterization of pendrin in a polarized cell system. Evidence for pendrin-mediated apical iodide efflux.Gillam MP, Sidhaye AR, Lee EJ, Rutishauser J, Stephan CW, Kopp P. J Biol Chem. 2004 Mar 26;279(13):13004-10. Epub 2004 Jan 8.
"Pendred's syndrome is
an autosomal recessive disorder characterized by sensorineural
deafness, goiter, and impaired iodide organification. It is
caused by mutations in the PDS/SLC26A4 gene that encodes pendrin.
Functionally, pendrin is a transporter of chloride and iodide in
Xenopus oocytes and heterologous mammalian cells and a
chloride/base exchanger in beta-intercalated cells of the renal
cortical collecting duct. The partially impaired thyroidal iodide
organification in Pendred's syndrome suggests a possible role of
pendrin in iodide transport at the apical membrane of thyroid
follicular cells, but experimental evidence for this concept is
lacking. The iodide transport properties of pendrin were
determined in polarized Madin-Darby canine kidney cells
expressing the sodium iodide symporter (NIS), pendrin, or NIS and
pendrin using a bicameral system-permitting measurement of iodide
content in the basal, intracellular, and apical compartments.
Moreover, we determined the functional consequences of two
naturally occurring mutations (L676Q and FS306>309X). In
polarized Madin-Darby canine kidney cells, NIS mediates uptake at
the basolateral membrane. Only minimal amounts of iodide reach
the apical compartment in the absence of pendrin. In cells
expressing NIS and pendrin, pendrin mediates transport of iodide
into the apical chamber. Wild type pendrin also mediates iodide
efflux in transiently transfected cells. In contrast, both
pendrin mutants lose the ability to promote iodide efflux. These
results provide evidence that pendrin mediates apical iodide
efflux from polarized mammalian cells loaded with iodide.
Consistent with the partial organification defect observed in
patients with Pendred's syndrome, naturally occurring mutations
of pendrin lead to impaired transport of iodide."
Pendred's syndrome: identification of the genetic defect a century after its recognition.Kopp P. Thyroid. 1999 Jan;9(1):65-9. Review. [abstract only]
"Pendred's syndrome is an autosomal recessive disease characterized by goiter and congenital sensorineural deafness. Most patients with Pendred's syndrome are euthyroid, but the perchlorate test is positive indicating an impaired iodide organification. The sensorineural deafness is typically associated with a malformation of the inner ear, referred to as Mondini cochlea. The incidence of Pendred's syndrome is thought to be as high as 7.5 to 10 in 100,000 individuals, and it has been estimated to account for about 10% of the cases with hereditary deafness. Linkage of Pendred's syndrome to chromosome 7q22-31.1 was first established in 1996, and the Pendred's syndrome gene (PDS gene) was cloned in 1997. The PDS gene encodes pendrin, a highly hydrophobic 780 aminoacid protein with 11 transmembrane domains. Its function is unknown. Sequence comparison reveals a very high homology to several sulfate transporters suggesting that it could be a sulfate or anion transporter. A wide spectrum of mutations in the PDS gene has now been associated with Pendred's syndrome. Molecular analysis of the PDS gene is useful to make a definite diagnosis in familial and sporadic cases with Pendred's syndrome, and will be helpful for determining the true prevalence of this disorder."
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