Molecular genetic study of frontoethmoidal encephalocele in Indonesia

印度尼西亚额筛脑膨出的分子遗传学研究

• 批准号: 13576023
• 负责人: MATSUO Masafumi
• 金额: $ 8.13万
• 依托单位: Kobe University Graduate School of medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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/en/grant/KAKENHI-PROJECT-13576023/
• 关键词: Frontoethmoidal encephalocele; Neural tube defects; 5, 10-methylenetetrahydrofolate reductase; SNPs; Homeobox genes; craniofacial formation; 前頭骨部〓骨部脳瘤; 疾患責任遺伝子; 疾患感受性遺伝子; 頭部形成ホメオボックス遺伝子; Neural tube defect

Frontoethmoidal encephalocele (FEE) is a neural tube defect (NID) characterized by a congenital bone defect in the anterior cranium and herniation of the intracranial mass through the defect. The Indonesian populations show high incidence of FEE. In 2001-2002, we studied FEE patients in Malang, East Java Province, Indonesia with a research group of Brawi jaya University. In this study, we investigated the background of the FEE families and carried out genetic analysis after obtaining informed consent.A mutation in the 5, 10-methylenetetrahydrofolate reductase gene (MTHFR) has been reported as a genetic risk factor for NIDs. To test the relationship between MTHFR and the development of FEE, we performed genomic screening of MTHFR substitutions mutations and polymorphisms in 13 patients and 8 mothers from 11 FEE families. Nucleotide substitutions (mutations of SNPs) detected were C121T, C677T, C1060T, A1298C, and G1793A. No significant differences were detected in the frequency of each n … More ucleotide substitution between patients or mothers and controls. In addition, none of the subjects tested were homozygous for T at nucleotide position 677. In conclusion, the MTHFR gene may not be associated with the development of FEE, although the number of FEE families analyzed in this study was very limited.We also studied the frequency of the C677T mutation in Indonesian Javanese. Both frequencies of the mutated allele and the mutated homozygotes were very low in the Javanese population. A hypothesis has been reported that low frequency of the C677T mutation is associated with the low incidence of NIDs in Africa. However, in Indonesian Javanese, a high incidence of a form of NID, FEE, has been seen in spite of a low frequency of the C677T mutation.Recently, the presence of compound mutants of the Alx3 and Alx4 homeobox genes in mice has shown severe craniofacial abnormalities. The Alx3/Alx4 double mutant mice shows a suggestive model of FEE, though no mutations were detected in the ALX4 gene in our FEE patients. The development of FEE may require a set of mutations in independent genes on the analogy of the Alx3/Alx4 double mutations were detected in the ALX4 gene in our FEE patients. The development of FEE may require a set of mutations in independent genes on the analogy of the Alx3/Alx4 double mutant mice. If so, it is much more complicated to determine the inheritance trait of FEE than a single gene disorder. Less

额筛脑膨出（FEE）是一种神经管缺陷（NID），其特征是前颅骨先天性骨缺损和颅内肿块通过缺损突出。印度尼西亚人口中 FEE 的发生率很高。 2001-2002年，我们与布拉维贾亚大学的一个研究小组一起对印度尼西亚东爪哇省玛琅的FEE患者进行了研究。在本研究中，我们调查了FEE家族的背景，并在获得知情同意后进行了遗传分析。5, 10-亚甲基四氢叶酸还原酶基因（MTHFR）的突变已被报道为NIDs的遗传危险因素。为了检验 MTHFR 与 FEE 发生之间的关系，我们对来自 11 个 FEE 家族的 13 名患者和 8 名母亲进行了 MTHFR 替代突变和多态性的基因组筛查。检测到的核苷酸取代（SNP 突变）为 C121T、C677T、C1060T、A1298C 和 G1793A。患者或母亲与对照之间每种核苷酸替代的频率没有检测到显着差异。此外，没有一个测试对象的677位核苷酸T是纯合的。总之，MTHFR基因可能与FEE的发展无关，尽管本研究中分析的FEE家族数量非常有限。我们还研究了印度尼西亚爪哇语中C677T突变的频率。在爪哇人群中，突变等位基因和突变纯合子的频率都非常低。据报道，有一种假设认为，C677T 突变的低频率与非洲 NID 的低发病率有关。然而，在印度尼西亚爪哇语中，尽管 C677T 突变频率较低，但 NID（FEE）的发病率却很高。最近，小鼠体内 Alx3 和 Alx4 同源盒基因复合突变体的存在已显示出严重的颅面异常。 Alx3/Alx4 双突变小鼠显示出提示性的 FEE 模型，尽管在我们的 FEE 患者中未检测到 ALX4 基因突变。 FEE 的发展可能需要独立基因中的一组突变，类似于我们的 FEE 患者中 ALX4 基因中检测到的 Alx3/Alx4 双突变。 FEE 的发展可能需要一组独立基因的突变，类似于 Alx3/Alx4 双突变小鼠。如果是这样，那么确定 FEE 的遗传性状比单基因疾病要复杂得多。较少的

项目成果

Sadewa AH, et al.: "The C677T Mutation in the Methylenetetrahydrofolate Reductase Gene among the Indonesian Javanese Population"Kobe. J. Med. Sci.. 48巻5号. 137-144 (2002)

Sadewa AH 等：“印度尼西亚爪哇人群中亚甲基四氢叶酸还原酶基因的 C677T 突变”Kobe. J. Sci.. Vol. 48，No. 5. 137-144 (2002)