Molecular analysis of the PDS gene in a nonconsanguineous Sicilian family with Pendred's syndrome.
OBJECTIVE
The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a chloride/iodide transporter expressed in the thyroid, the inner ear, and the kidney. In this study we performed clinical and molecular analyses in three siblings from a nonconsanguineous Sicilian family who presented with the clinical features of Pendred's syndrome. PATIENTS AND MOLECULAR ANALYSES: In two sisters and one brother, the clinical diagnosis of Pendred's syndrome was established based on the findings of sensorineural hearing loss and large goiters. Thyroid function tests, perchlorate discharge tests, thyroid ultrasound, and scintigraphy were performed in all affected individuals. Exons 2 to 21 of the PDS gene were amplified by polymerase chain reaction (PCR) and both strands were submitted to direct sequence analysis.


RESULTS
The clinical diagnosis of Pendred's syndrome was supported by a positive perchlorate discharge test in the three afflicted siblings. Direct sequence analysis of the PDS gene revealed that all three harbored one allele with a novel mutation 890delC leading to a frameshift mutation and premature stop codon at position 302 (FS297 > 302X). On the other allele, two of the siblings had a previously described transition 1226G > A, which results in the substitution of arginine by histidine at position 409 (R409H). In the index patient, no mutation could be identified on the other allele. In functional studies, these mutants lose the ability of pendrin to mediate iodide efflux.


CONCLUSIONS
All three patients included in this study presented with the classic Pendred syndrome triad. Two siblings were compound heterozygous for mutations in the coding region of the PDS gene. The third individual could have an unidentified mutation in a regulatory or intronic region of the PDS gene, or an identical phenotype caused by distinct pathogenic mechanisms.
Gillam
M P
MP
Division of Endocrinology, Metabolism, & Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Bartolone
L
L
Kopp
P
P
Benvenga
S
S
Bevenga
S
S
D000293:Adolescent; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006042:Goiter / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D010375:Pedigree; D012802:Sicily; D000076988:Sulfate Transporters
D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters