The present results question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome and support the use of a molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphological anomaly even in the absence of a thyroid goiter.
Loss of function mutations in pendrin protein cause Pendred syndrome, a disorder characterized by sensorineural deafness and a partial iodide organification defect that may lead to thyroid goiter.
Interestingly, molecular genetic testing showed that, whereas the elder sister is affected by PS, the younger sister has both PS (due to compound heterozygous SLC26A4 mutations) and RTH (due to a novel de novo heterozygous THRB mutation).
Therefore, in this study, we focused on the function of ten missense pendrin mutations (p.P123S (Pendred syndrome), p.M147V (NSEVA), p.K369E (NSEVA), p.A372V (Pendred syndrome/NSEVA), p.N392Y (Pendred syndrome), p.C565Y (NSEVA), p.S657N (NSEVA), p.S666F (NSEVA), p.T721M (NSEVA) and p.H723R (Pendred syndrome/NSEVA)) reported in Japanese patients, and analyzed their cellular localization and anion exchanger activity using HEK293 cells transfected with each mutant gene.
Recessive mutations of the SLC26A4 (PDS) gene on chromosome 7q31 can cause sensorineural hearing loss with goiter (Pendred syndrome) or non-syndromic autosomal recessive hearing loss (DFNB4).
Whilst these findings demonstrate molecular heterogeneity for PDS mutations associated with Pendred syndrome, this study would support the use of molecular analysis of the PDS gene in the assessment of families with congenital hearing loss.
Special interest has focused on four members of the SLC26 family that are associated with distinct recessive diseases: (i) Mutations in SLC26A2 lead to four different chondrodysplasias (diastrophic dysplasia, atelosteogenesis type II, achondrogenesis type IB and multiple epiphyseal dysplasia); (ii) SLC26A3 is associated with congenital chloride diarrhea; (iii) SLC26A4 is associated with Pendred syndrome and non-syndromic deafness, DFNB4; and (iv) SLC26A5 is defective in non-syndromic hearing impairment.
The expression of two recently identified iodide transporters, namely the sodium/iodide symporter (NIS) and pendrin, the product of the gene responsible for the Pendred syndrome (PDS), was studied in a series of various extra-thyroidal human tissues, and especially in those known to concentrate iodide.
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.
Mutations in the SLC26A4 gene, which encodes pendrin, cause congenital hearing loss as a manifestation of Pendred syndrome (PS) with an iodide organification defect or nonsyndromic enlarged vestibular aqueduct (NSEVA, DFNB4).
The presence of two mutant alleles of SLC26A4 is correlated with bilateral EVA and Pendred syndrome, whereas unilateral EVA and NSEVA are correlated with one (M1) or zero (M0) mutant alleles of SLC26A4.
These results support a novel dosage-dependent model for the molecular pathogenesis of PS and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery.
Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome.
Pendred's syndrome may account for up to 10% of the cases with hereditary hearing loss, and pendrin mutations have also been found in a kindred with non-syndromic deafness.
Molecular analysis of the PDS gene is useful to make a definite diagnosis in familial and sporadic cases with Pendred's syndrome, and will be helpful for determining the true prevalence of this disorder.
Mutation screening revealed two SLC26A4 mutant alleles in all 19 PS patients that were homozygous in two families and compound heterozygous in 12 families.