Phenotypes associated with replacement of His by Arg in the Pendred syndrome gene

Abstract

Background: Pendred syndrome is often associated with inner ear malformations, especially enlarged vestibular aqueduct (EVA). Recently, mutations in the Pendred syndrome gene (PDS) have been reported in patients with EVA, in addition to those with classical Pendred syndrome. Objective: The aim of this study was to investigate the genotype-phenotype correlations of PDS. Methods: Each of the 21 exons and flanking splice regions of PDS was analysed by direct DNA sequencing in nine patients with EVA; allele-specific amplification was performed to confirm the mutation. Genetic analyses were compared with thyroid function tests, perchlorate discharge tests, thyroid volume and pure-tone audiogram. Magnetic resonance imaging was used to determine the volume of the endolymphatic duct and sac of each patient. Results: A missense mutation, H723R, was identified in the homozygous state in three patients and in the heterozygous state in another three. Although none of the patients had goitre, increased serum thyroglobulin and an abnormal degree of iodide release were correlated with the number of mutant alleles identified. However, there was no relationship between the degree of hearing loss and the number of mutant alleles. Conclusion: The present study reveals that the number of mutant alleles correlates with the degree of subclinical thyroid abnormality, but not with the degree of hearing loss in Japanese patients with the PDS missense mutation H723R.

Iodide transport and breast cancer

“…Supporting these in vitro data, patients suffering Pendred syndrome, a disease where the gene-encoding pendrin (PDS) contains an inactivating mutation, display altered iodine organification (Sheffield et al 1996). However, more recently there have been questions as to pendrin's role in iodide transport as patients with biallelic PDS mutations, with sufficient iodide intake, displayed no altered thyroidal phenotype (Sato et al 2001) and pendrin knockout mice did not develop goitres and had normal thyroid function tests (Everett et al 2001). In lactating mammary glands, an iodide/anion exchanger that was sensitive to 4,4 0 -diisothiocyano-2,2 0 -stilbenedisulfonic acid (DIDS) was discovered (Shennan 2001) and was later identified as pendrin (Rillema & Hill 2003a).…”

Deafness Genes and Their Diagnostic Applications

“…These recurrent mutations are easy to screen using standard laboratory techniques. Therefore testing them is useful for families with a child with congenital or child- [Abe et al, 2000;Brobby et al, 1998;Denoyelle et al, 1997;Estivill et al, 1998a;Gasparini et al, 2000;Morell et al, 1998] Congenital (or childhood onset) autosomal recessive HI with only 1 mutant GJB2 allele GJB6 342del kb (in Spanish population but rare in Belgian population) Hilbert et al, 2002] Progressive HI with vestibular involvement COCH P51S (in Belgian and Dutch patients) [Fransen and Van Camp, 1999a] Autosomal dominant low-frequency HI WFS1 None, but mutations cluster in C-terminal protein domain [Cryns et al, 2002] Nonsyndromic hereditary HI associated with an enlarged vestibular aqueduct SLC26A4 H723R, IVS7-2A 1 G in Asian populations (both mutations are also found in patients with classical Pendred syndrome); several recurrent mutations are known for Pendred syndrome Park et al, 2003;Sato et al, 2001;Usami et al, 1999] Autosomal recessive nonsyndromic auditory neuropathy OTOF Q829X (in Spanish population) [Migliosi et al, 2002;Varga et al, 2003] Maternally inherited HI, aminoglycoside susceptibility 12S rRNA 1555A→G [Prezant et al, 1993;Usami et al, 1997] hood onset nonsyndromic sensorineural HI with normalhearing parents. However, in a relatively large fraction of patients with presumed autosomal recessive HI, only 1 mutant allele is detected.…”

“…In families from Western Europe and North America, 3 missense mutations and 1 splice site mutation (L236P, T416P, E384G and IVS8 + 1G1A) are found very frequently, and according to Coyle et al [1998], these mutations account for 74% of all PDS disease chromosomes. In German PDS families, the V138F mutation seems to be frequent [Borck et al, 2003] and in Asian patients with nonsyndromic HI and EVA the H723R and IVS7-2A1G variants are the most commonly reported mutations Park et al, 2003;Sato et al, 2001;Usami et al, 1999]. The latter 2 Cryns/Van Camp mutations have also been found in patients with classical Pendred syndrome [Coucke et al, 1999;].…”

Controversies Concerning the Role of Pendrin as an Apical Iodide Transporter in Thyroid Follicular Cells

“…It is generally thought that the development of hypothyroidism in patients with Pendred syndrome occurs under conditions of a low nutritional iodide intake [26][27][28][29][30]. For example, patients with Pendred syndrome from an iodide-deficient region from Northern Mexico have been found to have overt congenital hypothyroidism [31].…”

“…The fact that some individuals with biallelic mutations in the SLC26A4 gene have no or only a mild thyroidal phenotype [30], indicates that iodide crosses the apical membrane independently of pendrin through another iodide channel or unspecific channels. Thus, the relative importance of pendrin remains uncertain.…”