Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma.
Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na+/HCO3- cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5'-end of the kNBC1 gene (SLC4A4) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na+/HCO3- cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.
Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo.
Takashi
T
Igarashi
Department of Pharmacology and Toxicology, Kyourin University School of Medicine, Tokyo.
Jun
J
Inatomi
Department of Pediatrics, Faculty of Medicine, University of Tokyo, Tokyo.
Takashi
T
Sekine
Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, Tokyo.
George
G
Seki
Department of Genetics, Mitsubishi Yuka Bio-clinical Laboratories, Inc., Tokyo.
Mitsunobu
M
Shimadzu
Department of Genetics, Mitsubishi Yuka Bio-clinical Laboratories, Inc., Tokyo.
Fumiko
F
Tozawa
Department of Pediatrics, Faculty of Medicine, Kobe University, Kobe, Japan.
Yasuhiro
Y
Takeshima
Department of Pediatrics, Faculty of Medicine, Kobe University, Kobe, Japan.
Toru
T
Takumi
Department of Pediatrics, Faculty of Medicine, Kobe University, Kobe, Japan.
Toshikazu
T
Takahashi
Department of Pediatrics, Faculty of Medicine, Kobe University, Kobe, Japan.
Norishige
N
Yoshikawa
Department of Pediatrics, Faculty of Medicine, Kobe University, Kobe, Japan.
Hajime
H
Nakamura
Department of Pharmacology and Toxicology, Kyourin University School of Medicine, Tokyo.
Hitoshi
H
Endou
D000141:Acidosis, Renal Tubular / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics; D004262:DNA Restriction Enzymes; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005901:Glaucoma / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000502:physiology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D027982:Sodium-Bicarbonate Symporters
D002352:Carrier Proteins; D018389:Codon, Nonsense; D018076:DNA, Complementary; D012333:RNA, Messenger; D027982:Sodium-Bicarbonate Symporters; D004247:DNA; D004262:DNA Restriction Enzymes