Splice‐site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome

Medical and Molecular Genetics Center-IRO, Hospital Duran i Reynals, L'Hospitalet, Barcelona, Spain.
Human Mutation (Impact Factor: 5.14). 12/1999; 14(6):520-6. DOI: 10.1002/(SICI)1098-1004(199912)14:6<520::AID-HUMU11>3.0.CO;2-K
Source: PubMed


Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS) has been mapped to chromosome 7q22-q31, and encodes a chloride-iodide transport protein. We performed mutation analysis of individual exons of the PDS gene in one Spanish family that shows intrafamilial variability of the deafness phenotype (two patients with profound and one with moderate-severe deafness). We identified a new splice-site mutation affecting intron 4 of the PDS gene, at nucleotide position 639+7. RNA analysis from lymphocytes of the affected patients showed that mutation 639+7A-->G generates a new donor splice site, leading to an mRNA with an insertion of six nucleotides from intron 4 of PDS. Since the newly created donor splice site is likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the PDS gene in the cochlea may explain the variability in the deafness presentation.

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    • "Splice site and some missesnse mutations cause less severe degree of HL which may be progressive (Kitamura et al., 2000; Lopez-Bigas et al., 1999; Luxon et al., 2003) DFNB7 TMC1 Progressive HL in one family (de Heer et al., 2011) DFNB8 TMPRSS3 Hypomorphic alleles cause progressive HL (Hutchin et al., 2005; Scott et al., 2001; Veske et al., 1996; Weegerink et al., 2011) DFNB12 CDH23 Compound heterozygous mutations may cause progressive HL (Astuto et al., 2002) "

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    • "interfering with splicing regulatory elements such as exonic splicing enhancers [3] [4] [5] [6] [7] [8] [9]. Splicing mutations, thus, may play a more important role than previously though in human hereditary disease. "
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    • "In the last 3 years, more than 40 different PDS mutations have been reported in either homozygosity or compound heterozygosity in families with Pendreds syndrome (Everett et al., 1997; Coyle et al., 1998; Van Hauwe et al., 1998; Cremers et al., 1998; Coucke P et al., 1999; Kopp et al., 1999; Lopez-Bigas, 1999; Bogazzi et al., 2000; Fugazzola et al., 2000; Masmoudi, 2000). In the Figure 2, the position of each mutation along the putative pendrin structure is shown. "
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    ABSTRACT: 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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