title: Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis.
abstract: Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease with isolated pRTA, short stature and ocular abnormalities. We identified a novel homozygous deletion of nucleotide 2,311 adenine in the kidney type Na+/HCO3- cotransporter (kNBC1) cDNA in a patient with permanent isolated pRTA. This mutation is predicted to result in a frame shift at codon 721 forming a stop codon after 29 amino acids anomalously transcribed from the SLC4A4 gene. Cosegregation of this mutation with the disease was supported by heterozygosity in the parents of the affected patient. The absence of this mutation in 156 alleles of 78 normal individuals indicates that this mutation is related to the disease and is not a common DNA sequence polymorphism. When injected into Xenopus oocytes, the mutant cRNA failed to induce electrogenic transport activity. In addition, immunofluorescence and Western blot analysis failed to detect the expression of the full-length protein in mutant-injected oocytes. Our results expand the spectrum of kNBC1 mutations in permanent isolated pRTA with ocular abnormalities and increase our understanding of the renal tubular mechanism that is essential for acid-base homeostasis.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 112-8688, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Inatomi
authors.forename: Shoko
authors.initials: S
authors.lastname: Horita
authors.forename: Nancy
authors.initials: N
authors.lastname: Braverman
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekine
authors.forename: Hideomi
authors.initials: H
authors.lastname: Yamada
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Kawahara
authors.forename: Nobuo
authors.initials: N
authors.lastname: Moriyama
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kudo
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Shimadzu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: George
authors.initials: G
authors.lastname: Seki
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
mesh_terms: D000141:Acidosis, Renal Tubular / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D005124:Eye Abnormalities / Q000150:complications; D005455:Fluorescent Antibody Technique; D006720:Homozygote; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000503:physiopathology*; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics* / Q000378:metabolism*; D014981:Xenopus
chemical_list: D018076:DNA, Complementary; C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters