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

永久性孤立性肾近端小管酸中毒（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。我们报道了两个纯合失活错义突变（R298S和R510S）肾Na^+/HCO3^-共转运体（NBC-1a）基因（SLC4A4）在两例无亲缘关系的永久性分离pRTA合并青光眼、白内障和带状角膜病变患者（自然基因23:264-266,1999）。这次，我们从一个永久性分离的pRTA和双侧青光眼患者的外周淋巴细胞中筛选了NBC-1a cDNA，并发现了纯合突变，核苷酸234处C到T的转变，导致密码子29处形成停止密码子。这种纯合突变Q29X在患者SLC4A4独特的5'端被鉴定出来。该Q29X突变与该病共分离，并在受影响的母亲和父亲中鉴定出杂合性，在78名日本人的156个等位基因中没有该突变，表明该突变与该病直接相关，而不是常见的DNA序列多态性。这种无义突变预示着缺少1007个氨基酸的NBC-1a被截断，对NBC-1a的影响很可能是功能丧失。相反，这种突变预计不会对NBC-1b（胰腺NBC）产生影响。我们的研究结果有助于理解NBC-1a在pRTA和白内障、青光眼和带状角膜病变等眼部异常的病理生理学中的作用。

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.