Thyroid peroxidase: Evidence for disease gene exclusion in Pendred's syndrome

OBJECTIVE Pendred's syndrome is an association between congenital neurosensory deafness and goitre with abnormal discharge of iodide following perchlorate challenge, indicating a defect of iodide organification. Although Pendred's syndrome may cause up to 7.5% of all cases of congenital deafness, the molecular basis of the association between the hearing loss and the thyroid organification defect remains unknown. We chose to investigate the role of the thyroid peroxidase (TPO) gene as the genetic defect in Pendred's syndrome. DESIGN A highly informative variable number tandem repeat (VNTR), located 1.5 kb downstream of exon 10 of the TPO gene,was used to search for genetic linkage in multiple sibships affected by Pendred's syndrome. PATIENTS Seven kindreds were recruited from the uh, each with at least two affected members. We have also examined a large inbred Israeli family with two affected offspring and five unaffected children. MEASUREMENTS Individuals were assigned affected status based on the characteristic clinical features of Pendred's syndrome, namely the presence of congenital sensorineural hearing loss and the appearance in early life of a goitre. Additionally, at least one affected member from each sibship had a characteristic positive perchlorate discharge test (Morgans & Trotter, 1958). PCR amplification of genomic DNA at the TPO VNTR allowed assignment of genotypes to each individual and the calculation of a two-point LOD score. RESULTS In six of the nine sibships analysed we found obligatory recombination between TPO and Pendred's syndrome. Non-complementation observed in affected parents with an affected offspring excluded TPO in an affected sibship with genotype sharing and supports a hypothesis of genetic homogeneity for Pendred's syndrome. In two sibships, mutation of the TPO gene as the cause of Pendred's syndrome could not be excluded. CONCLUSIONS These data suggest that defects at the thyroid peroxidase locus on chromosome 2 are not the major cause of Pendred's syndrome.