Molecular genetic study of frontoethmoidal encephalocele in Indonesia

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 13576023
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 海外学術
• Research Field: Pediatrics
• Research Institution: Kobe University Graduate School of medicine
• Principal Investigator: MATSUO Masafumi Kobe University Graduate School of medicine Professor, 大学院・医学系研究科, 教授 (10157266)
• Co-Investigator(Kenkyū-buntansha): NISHIYAMA Kaoru Kobe University School of medicine Professor, 医学部, 教授 (00150061) ; NISHIO Hisahide Kobe University Graduate School of medicine Professor, 大学院・医学系研究科, 教授 (80189258) ; TAKESIMA Yasuhiro Kobe University Graduate School of medicine Assistant, 大学院・医学系研究科, 講師 (40281141) ; SHIRAKAWA Taku Kobe University School of medicine Associate Professor, 医学部, 助教授 (30171044)
• Project Period (FY): 2001 – 2002
• Keywords: Frontoethmoidal encephalocele / Neural tube defects / 5, 10-methylenetetrahydrofolate reductase / SNPs / Homeobox genes / craniofacial formation

Research Abstract

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 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.