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 abnor malities is a systemic disease involving short stature, isolated pRTA, ment al retardation, and ocular abnormalities. Kidney Na+/HCO3- cotransporter (k NBC1) cDNA from peripheral lymphocytes from a patient with permanent isolat ed pRTA and bilateral glaucoma was screened, and a novel homozygous mutatio n, namely a cytosine-to-thymine transition at nucleotide 234, which resulte d in the formation of a stop codon at codon 29, was identified. This homozy gous mutation, Q29X, was identified in the unique 5'-end of the kNBC1 gene (SLC4A4) of the patient. Cosegregation of this Q29X mutation with the disea se and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals i ndicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a trunca ted 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 fun ction. In contrast, the pancreatic Na+/NCO3- cotransporter of the patient i s not likely to be affected by this nonsense mutation. These results have i mplications for understanding the role of kNBC1 in the pathophysiologic pro cesses of pRTA associated with ocular abnormalities and mental retardation.