Identification of a novel gene responsible for hyperglycinemia

鉴定导致高甘氨酸血症的新基因

• 批准号: 13670779
• 负责人: KURE Shigeo
• 金额: $ 1.92万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670779/
• 关键词: hyperglycinemia; glycine cleavage system; disturbances in central nervous system; GCSH gene; transient hyperglycinemia; gene mutation; splicing error; グリシン開裂素系; グリシン脱炭酸素遺伝子; 遺伝子多型マーカー; イスラエル; 大家族; 常染色体劣性遺伝; 染色体マッピング

Transient neonatal hyperglycinemia (TNH) is clinically or biochemically indistinguishable from nonketotic hyperglycinemia at onset. In the case of TNH the elevated plasma and CFS glycine levels are normalized within 2-8 weeks. To elucidate the pathogenesis of TNH and idntification of a novel gene for hyperglycinemia we studied three patients by screening mutations in the genes that encode components of the glycine cleavage system (GCS). The GCS is a mitochondrial multi-enzyme system that consists of four individual components; P-protein, glycine decarboxylase; T-protein, aminomethyltransferase; H-protein, hydrogen carrier protein; L-protein, dihydrolipoamide dehydrogenase. P, T, H, and L-proteins were encoded by GLDC, AMT, GCSH, and GCSL genes, respectively. Several NKH-causing mutations have been identified in GLDC and AMT. No mutations have been identified in GCSH to date. Heterozygous mutations were identified in all of the three patients suggesting that TNH develops in some heterozygous carriers for nonketotic hyperglycinemia. We identified a splicing mutation of GCSH gene for the first time, indicating that GCSH gene is responsible for hyperglycinemia.

发作时，瞬时新生儿高血糖（TNH）与非酮高血糖症在临床或生化是无法区分的。在TNH的情况下，升高的血浆和CFS甘氨酸水平在2-8周内被标准化。为了阐明TNH的发病机理和高血糖基因的新基因的发病机理，我们通过在编码甘氨酸裂解系统（GCS）的基因中筛选突变，研究了三名患者。 GCS是一种线粒体多酶系统，由四个单独的组件组成。 P蛋白，甘氨酸脱羧酶； T蛋白，氨基甲基转移酶； H蛋白，氢载体蛋白； l蛋白，二氢丙酰胺脱氢酶。 P，T，H和L蛋白分别由GLDC，AMT，GCSH和GCSL基因编码。在GLDC和AMT中已经确定了几个引起NKH的突变。迄今为止，GCSH尚未确定突变。在所有三名患者中都鉴定出杂合突变，这表明某些杂合载体在非酮高血糖中血症的某些杂合载体中发展。我们首次确定了GCSH基因的剪接突变，表明GCSH基因负责高血糖血症。

项目成果

Kanno K et al.: "Lack of evidence for a significant association between nonsyndromic cleft lip with or without cleft palate and the retinoic acid receptor alpha gene in the Japanese population"J Hum Genet. 47. 269-274 (2002)

Kanno K 等人：“缺乏证据表明日本人群中伴有或不伴有腭裂的非综合征性唇裂与视黄酸受体 α 基因之间存在显着关联”J Hum Genet。

Kudo T, et al.: "Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness"Hum Mol Genet. (印刷中). (2003)

Kudo T 等人：“显性失活连接蛋白 26 的转基因表达导致 Corti 器官退化和非综合征性耳聋”Hum Mol Genet（出版中）。

Toone JR et al.: "Novel mutations in the P-protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non-ketotic hyperglycinemia)"Mol Genet Metab. 76. 243-249 (2002)

Toone JR 等人：“甘氨酸脑病（非酮症高甘氨酸血症）患者 P 蛋白（甘氨酸脱羧酶）基因的新突变”Mol Genet Metab。

Takahashi K et al.: "Heterogeneity of mutations in the glucose-t-phosphatase gene in Japanese patients with glycogen storage disease type Ia"Am J Med Genet. 92. 90-94 (2000)

Takahashi K 等人：“日本 Ia 型糖原累积病患者葡萄糖-t-磷酸酶基因突变的异质性”Am J Med Genet。

Aoki Y, et al.: "A novel mutation in glial fibrillary acidic protein (GFAP) in a patient with Alexander disease"Neuroscience Lett. 312. 71-74 (2001)

Aoki Y 等人：“亚历山大病患者中胶质原纤维酸性蛋白 (GFAP) 的新突变”《神经科学快报》。