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

永久性孤立性近端肾小管酸中毒（pRTA）伴眼部异常是一种全身性疾病，伴有身材矮小、孤立性pRTA和眼部异常。我们已经报道了两名无亲缘关系的日本患者的肾Na^+/HCO 3 ^-协同转运蛋白（NBC-1a）基因（SLC 4A 4）的两个纯合失活错义突变（R298 S和R510 S），这两名患者患有永久性孤立性pRTA，并伴有青光眼、白内障和带状角膜病变（Nature Genet 23：264-266，1999）。这一次，我们从一名患有永久性孤立性pRTA和双侧青光眼的患者的外周淋巴细胞中筛选了NBC-1a cDNA，并鉴定了纯合突变，即核苷酸234处的C至T转换，导致在密码子29处形成终止密码子。该纯合突变Q29 X在患者的SLC 4A 4的独特5'端中被鉴定。该Q29 X突变与该病共分离，在患病母亲和父亲中存在杂合性，并且在来自78个日本个体的156个等位基因中不存在该突变，表明该突变与该病直接相关，并且它不是常见的DNA序列多态性。这种无义突变预测了缺少1，007个氨基酸的截短NBC-1a，并且对NBC-1a的影响可能是功能丧失。相反，该突变预测对NBC-1b（胰腺NBC）没有影响。我们的研究结果对于理解NBC-1a在pRTA和眼部异常（如白内障、青光眼和带状角膜病变）的病理生理学中的作用具有意义。

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.