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

伴有眼部异常的永久性孤立性近端肾小管酸中毒患者致病基因的鉴定

• 批准号: 11670741
• 负责人: IGARASHI Takashi
• 金额: $ 2.24万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670741/
• 关键词: Na^+; HCO3^- cotransporter; SLC4A4; proximal renal tubular acidosis; short stature; glaucoma; missense mutation; nonsense mutation; HCO3^- cotransporter; SLC4AC; 白内障; 帯状角膜変性症

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.

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。我们报道了两名患有青光眼、白内障和带状角膜病的永久分离性 pRTA 的无关日本患者中肾 Na^+/HCO3^- 协同转运蛋白 (NBC-1a) 基因 (SLC4A4) 的两个纯合失活错义突变（R298S 和 R510S）（Nature Genet 23：264-266，1999）。这次，我们从患有永久性分离性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，即第234位核苷酸处的C到T转换，导致第29号密码子处形成终止密码子。这种纯合突变Q29X是在SLC4A4的独特5'末端中鉴定的。 病人。该Q29X突变与该疾病的共分离以及受影响的母亲和父亲的杂合性被确定，78名日本个体的156个等位基因中不存在该突变，表明该突变与该疾病直接相关，并且它不是常见的DNA序列多态性。这种无义突变预示着 NBC-1a 会被截短，缺少 1,007 个氨基酸，而对 NBC-1a 的影响很可能是功能丧失。相比之下，这种突变预计不会对 NBC-1b（胰腺 NBC）产生影响。我们的结果对于理解 NBC-1a 在 pRTA 病理生理学和白内障、青光眼和带状角膜病等眼部异常中的作用具有重要意义。

项目成果

Igarashi T: "Unraveling the molecular basis of hereditary renal tubular acidosis."Clin Exp Nephrol. (in print). (2001)

Igarashi T：“揭示遗传性肾小管性酸中毒的分子基础。”Clin Exp Nephrol。

Igarashi T, Inatomi J: "A novel nonsense mutation in the Na+/HCO_3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma."J Am Soc Nephrol. (in press).

Igarashi T、Inatomi J：“患有永久性孤立性近端肾小管性酸中毒和双侧青光眼的患者的 Na /HCO_3- 协同转运蛋白基因 (SLC4A4) 中出现了一种新的无义突变。”J Am Soc Nephrol。

Shiohara M, Igarashi T: "Genetic and long term data on a patient with permanent isolated proximal renal tubular acidosis."Eur J Pediatr. 159(12). 892-894 (2000)

Shiohara M、Igarashi T：“永久性孤立性近端肾小管酸中毒患者的遗传和长期数据。”Eur J Pediatr。

Igarashi T: "A novel nonsense mutation in the Na^+/HCO3^-cotransportor gene in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma."J Am Soc Nephrol. (in print). (2001)

Igarashi T：“患有永久性孤立性近端肾小管性酸中毒和双侧青光眼的患者的 Na^/HCO3^-协同转运蛋白基因中出现了一种新的无义突变。”J Am Soc Nephrol。

Igarashi T, et al.: "Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities"Nature Genet. 23(11). 264-266 (1999)

Igarashi T 等人：“SLC4A4 突变导致永久性孤立性近端肾小管酸中毒并伴有眼部异常”Nature Genet。