Differential Diagnosis between Pendred and Pseudo-Pendred Syndromes: Clinical, Radiologic, and Molecular Studies

Fugazzola, Laura; Cerutti, Nadia; Mannavola, Deborah; Crinò, Antonino; Cassio, Alessandra; Gasparoni, P; Vannucchi, Guia; Beck‐Peccoz, Paolo

doi:10.1203/00006450-200204000-00013

Cited by 63 publications

(52 citation statements)

References 42 publications

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“…These data are consistent with the phenotype observed in the respective patients. The missense mutation R409H has been associated with PS in several cohorts and has been shown to impair pendrin function (28)(29)(30)(31), in agreement with the phenotype resulting from the compound heterozygosis described in the affected members.…”

Section: Discussionsupporting

confidence: 66%

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

et al. 2007

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Objective: Pendred syndrome (PS) is characterized by the association of sensorineural hearing loss (SNHL) and a partial iodide organification defect at the thyroid level. It is caused by mutations in the SLC26A4 gene. The encoded transmembrane protein, called pendrin, has been found to be able to transport chloride and other anions. Design: The aim of the present study was to characterize a family with PS, which shows a strong intrafamilial phenotypic variability, including kidney atrophy in one member. The age of disease-onset was significantly different in all three affected siblings, ranging from 2 to 21 years for thyroid alterations and from 1.5 to 11 years for SNHL. Methods: Clinical and genetic studies were carried out in affected siblings. The functional activity of the novel duplication found was studied by a fluorimetric method in a human renal cell line (HEK293 Phoenix) in which the protein was overexpressed. Results: All three siblings were found to be compound heterozygotes for the missense mutation (1226GOA, R409H) and for a novel 11 bp duplication (1561_1571CTTGGAATGGC, S523fsX548). The latter mutation creates a frameshift leading to the loss of the entire carboxy-terminus domain. Functional studies of this mutant demonstrated impaired transport of chloride and iodide when expressed in HEK 293 Phoenix cells, when compared with wild type pendrin. Conclusions: A novel 11 bp duplication was found in a family with Pendred syndrome, showing a high intrafamilial phenotypic variability. An impaired transmembrane anionic transport of the mutated SLC26A4 protein was demonstrated in functional studies using a heterologous cell system.

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Section: Discussionsupporting

confidence: 66%

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

et al. 2007

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“…12,14 The mutational spectrum in Spain is similar to those of the Italian and French populations, sharing 12 of the SLC26A4 alleles with the French 13 and four with the Italian population. 15 However, in our population the most frequent mutation is the novel p.Q514K found in six alleles (17%) that derives from a common founder. By means of a comprehensive genetic analysis, we have identified the first case of a de novo mutation c.1238A4C (p.Q413P) in the proband from a PS family that showed no apparent segregation with the DFNB4 locus.…”

Section: Discussionmentioning

confidence: 65%

A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.

et al. 2008

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Pendred syndrome (PS) and DFNB4, a non-syndromic sensorineural hearing loss with enlargement of the vestibular aqueduct (EVA), are caused by mutations in the SLC26A4 gene. Both disorders are recessive, and yet only one mutated SLC26A4 allele, or no mutations, are identified in many cases. Here we present the genetic characterization of 105 Spanish patients from 47 families with PS or non-syndromic EVA and 20 families with recessive non-syndromic hearing loss, which segregated with the DFNB4 locus. In this cohort, two causative SLC26A4 mutations could be characterized in 18 families (27%), whereas a single mutated allele was found in a patient with unilateral hearing loss and EVA in the same ear. In all, 24 different causative mutations were identified, including eight novel mutations. The novel p.Q514K variant was the most prevalent mutation in SLC26A4, accounting for 17% (6/36) of the mutated alleles identified in this study, deriving from a founder effect. We also characterized a novel multiexon 14 kb deletion spanning from intron 3 to intron 6 (g.8091T_22145Cdel). This study also revealed the first case of a de novo recessive mutation p.Q413P causing PS that arose in the proband's paternal allele, the maternal one carrying the p.L445W. The relevance of our results for genetic diagnosis of PS and non-syndromic EVA hearing loss is discussed.

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“…4E). Ci-Slc26aα R444C, analogous to R409P also from patients with Pendred syndrome (29,30), partially rescued the defective lumen formation phenotype (Fig. 4C).…”

Section: Transport Activity Of Ci-slc26aα Is Essential For Its In Vivmentioning

confidence: 85%

Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

Deng

Nies

Feuer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Lumen formation is a critical event in biological tube formation, yet its molecular mechanisms remain poorly understood. Specifically, how lumen expansion is coordinated with other processes of tubulogenesis is not well known, and the role of membrane transporters in tubulogenesis during development has not been adequately addressed. Here we identify a solute carrier 26 (Slc26) family protein as an essential regulator of tubulogenesis using the notochord of the invertebrate chordate Ciona intestinalis as a model. Ci-Slc26aα is indispensable for lumen formation and expansion, but not for apical/luminal membrane formation and lumen connection. Ci-Slc26aα acts as an anion transporter, mediating the electrogenic exchange of sulfate or oxalate for chloride or bicarbonate and electroneutral chloride:bicarbonate exchange. Mutant rescue assays show that this transport activity is essential for Ci-Slc26aα's in vivo function. Our work reveals the consequences and relationships of several key processes in lumen formation, and establishes an in vivo assay for studying the molecular basis of the transport properties of SLC26 family transporters and their related diseases. Biological tubular systems serve essential functions in embryogenesis, organogenesis, and adult physiology. The development of biological tubes is an interesting paradigm not only for biologists, but also for physicians, given that many devastating diseases are caused by failure of proper tubulogenesis or malfunction of tubular structures (1). A biological tube, in its simplest configuration, is composed of an epithelium enclosing a lumen. The tubular epithelium can either arise from a preexisting epithelium by wrapping or budding, or develop de novo from nonepithelial cells. In the latter case, nonepithelial cells undergo a mesenchymal-to-epithelial transition and become polarized, with a portion of the cell membrane, the apical domain, coming into direct contact with the future lumen (2). Exocytosis at the apical/luminal domain contributes to both apical membrane biogenesis and initial lumen formation.Recently, several transmembrane proteins, including transporters, pumps, and channels localized in the developing tubular epithelia, have been implicated in lumen expansion and tube size control (3). Among these, claudin and Na + K + -ATPase regulate lumen size in the development of the zebrafish gut (4) and the Drosophila trachea (5, 6) through their junctional activity. Interestingly, at least for Na + K + -ATPase, its pumping activity is dispensable (5). A bona fide apical transporter has not yet been identified and implicated in lumen expansion.Transepithelial ion transport is critically important for luminal fluid secretion and absorption in many tubular structures. The solute carrier 26 (SLC26) sulfate transporters, so-called because the first member, SLC26A1, was identified as a liver SO 4 2− transporter (7), compose a family of multidomain transmembrane anion exchangers capable of transporting a wide range of monovalent and divalent anions (8). Most ...

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Differential Diagnosis between Pendred and Pseudo-Pendred Syndromes: Clinical, Radiologic, and Molecular Studies

Cited by 63 publications

References 42 publications

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.

Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

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