Two missense mutations in SLC26A4 gene: a molecular and functional study.

[pendred syndrome]

Mutations in the SLC 26 A 4 gene encoding pendrin , an anion transporter , are responsible for non-syndromic hearing loss (HL ) (DFNB 4 ) and Pendred syndrome (PS ). PS is a genetic disorder that causes early HL and affects the thyroid gland . Here , we report eight Tunisian families affected with profound HL . Clinical investigations revealed goiter in few patients . Genotyping using microsatellite makers showed linkage to SLC 26 A 4 , and missense mutations p .L 445 W and p .M 147 T were identified by sequencing and polymerase chain reaction-restriction fragment length polymorphism . The p .L 445 W mutation segregated in seven families and haplotype analysis suggested its founder effect . In order to understand the molecular pathogenic mechanisms of p .L 445 W and p .M 147 T mutations , SLC 26 A 4 wild-type and mutant cDNA constructs were transiently expressed in COS 7 cells and several human cell lines including Thyroid 8305 C cells . Reverse transcription-PCR , western blot and immunofluorescence demonstrated that these two mutations abolished complex glycosylation of pendrin and prevented its targeting to the plasma membrane .

Diseases
Validation

Diseases presenting "hearing loss" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

benign recurrent intrahepatic cholestasis

canavan disease

cohen syndrome

congenital toxoplasmosis

dentinogenesis imperfecta

fabry disease

familial mediterranean fever

heparin-induced thrombocytopenia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

neonatal adrenoleukodystrophy

pendred syndrome

von hippel-lindau disease

wolf-hirschhorn syndrome

This symptom has already been validated