title: Mutations and variants of the epithelial sodium channel gene in Liddle's syndrome and primary hypertension.
abstract: Liddle's syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel beta- or gamma-subunits. These mutations delete or alter a conserved proline-rich amino acid sequence referred to as the PY-motif. We report here a Liddle's syndrome family with a betaArg564X mutation with a premature stop codon deleting the PY-motif of the beta-subunit. This family shows marked phenotypic variation in blood pressure, serum potassium levels, and age of onset of hypertension. Given the similarity with primary hypertension, changes in the C termini of the beta- or gamma-subunits may contribute to the development of primary hypertension or to hypertension associated with diabetic nephropathy. Accordingly, the coding sequences for the cytoplasmic C termini of the beta- and gamma-subunits were screened for mutations with the use of polymerase chain reaction, single-strand conformation polymorphism, and direct DNA sequencing in 105 subjects with primary hypertension and 70 subjects with diabetic nephropathy. One frequent polymorphism was identified, but its frequency did not differ among subjects with primary hypertension, subjects with diabetic nephropathy, or control subjects. Two of the 175 subjects with primary hypertension or diabetic nephropathy showed variants that were not present in 186 control subjects. None of the variants changed the PY-motif sequence. In conclusion, a betaArg564X mutation is the likely cause of Liddle's syndrome in this Swedish family, but it is unlikely that mutations in the beta- and gamma-subunit genes of the epithelial sodium channel play a significant role in the pathogenesis of primary hypertension or diabetic nephropathy.
authors.affiliation: Department of Endocrinology, Lund University, Malmö, Sweden. olle.melander@endo.mas.lu.se
authors.forename: O
authors.initials: O
authors.lastname: Melander
authors.forename: M
authors.initials: M
authors.lastname: Orho
authors.forename: J
authors.initials: J
authors.lastname: Fagerudd
authors.forename: K
authors.initials: K
authors.lastname: Bengtsson
authors.forename: P H
authors.initials: PH
authors.lastname: Groop
authors.forename: I
authors.initials: I
authors.lastname: Mattiasson
authors.forename: L
authors.initials: L
authors.lastname: Groop
authors.forename: U L
authors.initials: UL
authors.lastname: Hulthén
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: D015222:Sodium Channels