Identification of diseasen causing gene in patients with permanent isolated proximal renal tubular acidosis with ocular abnormalities

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Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease with short stature, isolated pRTA and ocular abnormalities. We have reported two homozygous inactivating missense mutations (R298S and R510S) of kidney Na^+/HCO3^- cotransporter (NBC-1a) gene (SLC4A4) in two unrelated Japanese patients with permanent isolated pRTA with glaucoma, cataract, and bandkeratopathy (Nature Genet 23 : 264-266, 1999). This time, we screened the NBC-1a cDNA from the peripheral lymphocyte of a patient with permanent isolated pRTA and bilateral glaucoma and have identified homozygous mutation, C to T transitions at nucleotide 234, resulting in the formation of stop codon at codon 29. This homozygous mutation, Q29X, was identified in the unique 5' end of SLC4A4 of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the affected mother and father were identified, and the absence of this mutation in 156 alleles from 78 Japanese individuals indicated that this mutation is directly related to the disease and it is not a common DNA sequence polymorphism. This nonsense mutation predicts truncated NBC-1a that lacks the 1,007 amino acids, and the effect up on NBC-1a is likely to be a loss of function. In contrast, this mutaton predicts not to have an effect upon NBC-1b (pancreas NBC). Our result have implications for understanding the role of NBC-1a in the pathophysiology of pRTA and ocular abnormalities such as cataracts, glaucoma and bandkeratopathy.