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Fugazzola
Fast fluorometric method for measuring pendrin (SLC26A4) Cl-/I- transport activity.Dossena S, Rodighiero S, Vezzoli V, Bazzini C, Sironi C, Meyer G, Furst J, Ritter M, Garavaglia ML, Fugazzola L, Persani L, Zorowka P, Storelli C, Beck-Peccoz P, Botta G, Paulmichl M. Cell Physiol Biochem. 2006;18(1-3):67-74. Epub 2006 Aug 15.
"Malfunction of the SLC26A4 protein leads to Pendred syndrome, characterized by sensorineural hearing loss, often associated with mild thyroid dysfunction and goiter. It is generally assumed that SLC26A4 acts as a chloride/anion exchanger, which in the thyroid gland transports iodide, and in the inner ear contributes to the conditioning of the endolymphatic fluid. Here we describe a fast fluorometric method able to be used to functionally scrutinize SLC26A4 and its mutants described in Pendred syndrome. The validation of the method was done by functionally characterizing the chloride/iodide transport of SLC26A4, and a mutant, i.e. SLC26A4(S28R), which we previously described in a patient with sensorineural hearing loss, hypothyroidism and goiter. Using the fluorometric method we describe here we can continuously monitor and quantify the iodide or chloride amounts transported by the cells, and we found that the transport capability of the SLC26A4(S28R) mutant protein is markedly reduced if compared to wild-type SLC26A4."
The expression of wild-type pendrin (SLC26A4) in human embryonic kidney (HEK 293 Phoenix) cells leads to the activation of cationic currents.Dossena S, Maccagni A, Vezzoli V, Bazzini C, Garavaglia ML, Meyer G, Furst J, Ritter M, Fugazzola L, Persani L, Zorowka P, Storelli C, Beck-Peccoz P, Botta G, Paulmichl M. Eur J Endocrinol. 2005 Nov;153(5):693-9.
"OBJECTIVE: The SLC26A4 protein (pendrin) seems to be involved in the exchange of chloride with other anions, therefore being responsible for iodide organification in the thyroid gland and the conditioning of the endolymphatic fluid in the inner ear. Malfunction of SLC26A4 leads to Pendred syndrome, characterized by mild thyroid dysfunction often associated with goiter and/or prelingual deafness. The precise function of the SLC26A4 protein, however, is still elusive. An open question is still whether the SLC26A4-induced ion exchange mechanism is electrogenic or electroneutral. Recently, it has been shown that human pendrin expressed in monkey cells leads to chloride currents.
METHODS: We overexpressed the human SLC26A4 isoform in HEK293 Phoenix cells and measured cationic and anionic currents by the patch-clamp technique in whole cell configuration.
RESULTS: Here we show that human pendrin expressed in human cells does not lead to the activation of chloride currents, but, in contrast, leads to an increase of cationic currents.
CONCLUSION: Our experiments suggest that the SLC26A4-induced chloride transport is electroneutral when expressed in human cellular systems."
Differential diagnosis between Pendred and pseudo-Pendred syndromes: clinical, radiologic, and molecular studies.Fugazzola L, Cerutti N, Mannavola D, Crino A, Cassio A, Gasparoni P, Vannucchi G, Beck-Peccoz P. Pediatr Res. 2002 Apr;51(4):479-84. [abstract only]
"The disease gene for Pendred syndrome has been recently characterized and named PDS. It codes for a transmembrane protein called pendrin, which is highly expressed at the apical surface of the thyroid cell and functions as a transporter of chloride and iodide. Pendrin is also expressed at the inner ear level, where it appears to be involved in the maintenance of the endolymph homeostasis in the membranous labyrinth, and in the kidney, where it mediates chloride-formate exchange and bicarbonate secretion. Mutations in the PDS gene and the consequent impaired function of pendrin leads to the classic phenotype of Pendred syndrome, i.e. dyshormonogenic goiter and congenital sensorineural hearing loss. In the present study, we performed a detailed clinical, radiologic, and molecular analysis of six families presenting with clinical diagnosis of Pendred syndrome. In two families a homozygous pattern for PDS mutations was found, whereas the affected members of the other four families were compound heterozygotes. One family did not harbor PDS mutations. Among the four novel mutations described, one is a transversion in exon 2 (84C>A), leading to the substitution S28R. Two other novel mutations lie in exon 4 (398T>A) and in exon 16 (1790T>C), leading to the substitutions S133T and L597S, respectively. The fourth novel mutation (1614+1G>A) is located in the first base pair of intron 14, probably affecting the splicing of the PDS gene. Clinically, all patients had goiter with positive perchlorate test, hypothyroidism, and severe or profound sensorineural hearing loss. In all the individuals harboring PDS mutations, but not in the family without PDS mutations, inner ear malformations, such as enlargement of the vestibular aqueduct and of the endolymphatic duct and sac, were documented. The pseudo-Pendred phenotype exhibited by the family without PDS mutations is likely caused by an autoimmune thyroid disease associated with a sensorineural hearing loss of different origin."
The role of pendrin in iodide regulation.Fugazzola L, Cerutti N, Mannavola D, Vannucchi G, Beck-Peccoz P. Exp Clin Endocrinol Diabetes. 2001;109(1):18-22. Review.
"Recent advances in human genetics have catalyzed the attention on Pendred's syndrome and its disease-gene, PDS. Studies on the expression of the PDS gene and on the function of its encoded protein, which has been named pendrin, are currently in progress. Consistent with the Pendred's syndrome phenotype, which is characterized by thyroid dysfunction associated to deafness, PDS expression has been demonstrated in the thyroid and in the inner ear. Despite its high homology to known sulfate transporters, pendrin has been shown to transport iodide and chloride, but not sulfate. Thus, it is probably devoted to regulate, at the apical membrane where it has been immunolocalized, the flux of iodide from the thyroid cell to the colloid space. The function of pendrin in the inner ear is not well understood, but it seems to function also at this level as an anion transporter. Indeed, a pronounced PDS expression has been detected in structures of the inner ear, such as the membranous labyrinth and the endolymphatic duct and sac. At this level, the possible role of pendrin could be the maintenance of the appropriate ionic composition of the endolymph. Although many questions remain to be answered, these recent achievements concerning the putative role of pendrin aid to better understand the genetic basis of the peculiar phenotype of Pendred's syndrome, which associate the dysfunction of two so different organs such as the thyroid and the inner ear."
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