Goitrous Congenital Hypothyroidism and Hearing Impairment Associated with Mutations in the TPO and SLC26A4/PDS Genes

Pfarr, Nicole; Borck, Guntram; Turk, Andrew T.; Napiontek, Ulrike; Keilmann, Annerose; Müller‐Forell, Wibke; Kopp, Peter; Pohlenz, Joachim

doi:10.1210/jc.2006-0142

Cited by 40 publications

(46 citation statements)

References 16 publications

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“…These findings are consistent with the functional data published so far, with one exception. Pfarr et al (21) described an allelic variant (R776C) that, on a functional level, is indistinguishable from controls. However, this particular arginine is located on the extreme C terminus of SLC26A4 (a 780 aa protein).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the transformation of two allelic variants (V88I and L597S) that were not functionally different compared to WT SLC26A4, into mutations fitting the proline/fixed charge role (i.e., V88P and L597P), resulted in the annihilation of transport activity. Although, it is important to note that mutations that do not enter into this proline/fixed charge role can be functionally detrimental or without functional implication (15,20,21,26,27). In these cases, only functional tests can unambiguously distinguish between different SLC26A4 gene mutations in SNPs and those mutations that actually cause a reduced function and ultimately disease symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…However, two of them (V609G and G740S) were previously described in the National Center for Biotechnology Information database as SNPs. In addition, it was previously shown that R776C did not compromise SLC26A4 transport function (21). Therefore, the transport ability of E29Q, D724G, V88I, and L597S were tested in the present study.…”

Section: Slc26a4 Three Of Them (F354s L597smentioning

confidence: 92%

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Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Pera

Dossena

Rodighiero³

et al. 2008

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

105

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Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests.ion transport physiology ͉ genotype-phenotype correlation P endred syndrome (PS) (OMIM#274600) (1) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) (2) to Mondini malformation (3), combined with deficient iodide organification in the thyroid gland, as demonstrated by the positive perchlorate discharge test in affected individuals (4-7). Another form of SNHL associated with EVA, however, showing normal thyroid function, is called nonsyndromic EVA (ns-EVA) (OMIM#600791). The clinical features of PS are the consequence of impaired pendrin function (1), a protein encoded by the SLC26A4 gene (NM 000441). It is a member of the multifunctional anion transporter family SLC26, which mediates the exchange of anions including Cl Ϫ , HCO 3 Ϫ , OH Ϫ , I Ϫ , or formate (8). Pendrin seems to be responsible for the efflux of iodide in thyrocytes (9-11), and for mediating Cl Ϫ /HCO 3 Ϫ exchange in the kidney cortex (12) and inner ear. In the latter, pendrin is involved in the conditioning of endolymphatic fluid, presumably because of HCO 3 Ϫ secretion (13), thereby modifying inner ear acid-base homeostasis. A variable feature of PS is the development of goitre (apparent in only about 50% of the affected individuals). At the thyroid level, the role of pendrin is not conclusive. The transporter could act as an iodide transporter at the apical membrane of thyroid cells and impaired function could therefore lead to the iodide organification defect observed in PS patients (10,11,(14)(15)(16). PS seems to be linked to bi-allelic mutations of the SLC26A4 genes. ns-EVA is genetically more heterogeneous relative to PS, and a...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Slc26a4 Three Of Them (F354s L597smentioning

confidence: 92%

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Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Pera

Dossena

Rodighiero³

et al. 2008

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

105

View full text Add to dashboard Cite

show abstract

“…These variants, together with a variant (p.R776C) for which previous functional studies led to contradictory 500 different sequence alterations of the pendrin gene have been reported to date, but most of the corresponding protein variants miss a precise functional and molecular characterization (10). In the absence of careful genetic and functional assessments, two factors, i.e., the clinical condition of pseudoPendred syndromes (the association of deafness and goiter with no pendrin mutations [11][12][13][14][15]) and the existence of pendrin variants with no functional impairment (10), could lead to an incorrect assignment of the genetic cause of the disease.…”

Section: Patientsmentioning

confidence: 99%

Reduction of Cellular Expression Levels Is a Common Feature of Functionally Affected Pendrin (SLC26A4) Protein Variants

Moraes

Bernardinelli

Zocal

et al. 2016

Mol Med

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“…Because defects in DUOX2 result in lack of H 2 O 2 , this protein is essential for thyroid hormone synthesis. Evidence for the involvement of DUOX2 in thyroid hormonogenesis came from the identification of naturally occurring mutations; biallelic homozygous or compound heterozygous DUOX2 mutations lead to goitrous CH (29,53,54), whereas monoallelic nonsense defects cause transient CH (29,31) although biallelic DUOX2 mutations have also been reported recently in transient CH (55). Up to 23 DUOX2 mutations have been identified in patients with congenital hypothyroidism (29,(55)(56)(57).…”

Section: Thyroid Hormone Synthesis and The Genes Involved In The Processmentioning

confidence: 99%

Congenital Hypothyroidism and Thyroid Cancer

Zou¹,

Shi²

2012

A New Look at Hypothyroidism

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Goitrous Congenital Hypothyroidism and Hearing Impairment Associated with Mutations in the TPO and SLC26A4/PDS Genes

Cited by 40 publications

References 16 publications

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Reduction of Cellular Expression Levels Is a Common Feature of Functionally Affected Pendrin (SLC26A4) Protein Variants

Congenital Hypothyroidism and Thyroid Cancer

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