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Mutation Analysis of Forkhead Transcriptional Factor 2 (FOXL2) in a Five-generation Chinese Family with BPES Type Ⅰ

Author: ZhangYingYing
Tutor: ShiHuiRong
School: Zhengzhou University
Course: Obstetrics and Gynaecology
Keywords: BPES FOXL2 gene Mutation analysis
CLC: R394
Type: Master's thesis
Year: 2007
Downloads: 71
Quote: 1
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Abstract

Blepharophimosis inverted transformation epicanthus and ptosis syndrome (Blepharophimosis-ptosis-epicanthus inversus syndrome, BPES) is a rare autosomal dominant genetic disease, the incidence in the general population is about 1 / 100,000. Clinical blepharophimosis, the inverted transformation epicanthus and ptosis triad as the main feature. The small number of cases there are other anomalies, such as mental retardation, developmental delays, heart defects, small head and low set ears. Vonammon first described the disease in 1841. BPES can be divided into two types: type Ⅰ patients in addition to typical BPES facial features, female patients of infertility, primary amenorrhea or early menopause, a small uterus and premature ovarian failure, male patients fertility, but these a trait passed on to the next generation. Type II patients to both male and female fertility. Studies have shown that FOXL2 gene is located in 3q23 of the pathogenesis of the disease gene BPES I type and type II patients FOXL2 gene mutations can be detected. FOXL2 gene by a single long 2.7kb exon. Its encoded protein belongs to a large family of forkhead transcription factor, is composed of 376 amino acids, which contains a forkhead DNA-binding domain of 101 amino acids, and position in the region 54 ~ 152 residues. The downstream Here there is a separation of this function is unclear polyalanine peptides. Related the polyalanine peptides may inhibit the transcriptional activity. FOXL2 gene is a human autosomal genes play an important role in the first confirmed in ovarian function to maintain and ovarian differentiation. To date, the clinical no effective treatment the BPES Ⅰ female patients with infertility. Although the application of plastic surgery can correct BPES patients the eye and facial deformity, so as to improve its appearance, but the BPES patients generally eyesight affected, some associated with varying degrees of the disease in other systems of the body, so that patients and their families to bear the physical, mental, and multiple economic pain. In addition, the large variability of the clinical phenotype of patients with the disease, also brought some difficulties to the clinical diagnosis, Mendelian patients next generation recurrence risk was 50%, so BPES patients, genetic counseling is particularly important. Prenatal diagnosis of cytogenetic and genetic analysis. Patients karyotype normal pregnancy do cytogenetic investigation. But normal karyotype, can only be done through genetic analysis of prenatal diagnosis. Therefore, the application of genetics method for detection of the BPES pathogenic gene FOXL2 mutation type of prenatal diagnosis of the disease. The purpose of the patients from 5 generations of continuous pass the type Ⅰ the BPES everybody Department of FOXL2 gene mutation study, to find the mutation site. Provide guidance and theoretical basis for further genetic counseling. Method 1. Extraction affected individuals and the family Ⅳ 8 and Ⅲ 3 of the outer peripheral blood karyotype analysis. Detection of patients in the family is the presence of chromosomal deletions. 2. Classic salting extraction of patients in the family and come to my hospital healthy normal human peripheral blood genomic DNA and DNA purification and quantification. 3. References designed four pairs of primers for PCR amplification of the coding region of the FOXL2 gene. 4. Direct sequencing of the amplified product and detecting the presence of mutations and mutation sites. 5. Polyacrylamide electrophoresis further verify the results of the direct sequencing. Results 1. The pedigree analysis results show that the BPES pedigree autosomal dominant, and this pedigree BPES Ⅰ type. 2. Chromosome test showed that patients in the pedigree Ⅳ 8 and Ⅲ 3 were normal male karyotype: 46, XY and normal female chromosome karyotype: 46, XX. 3. Direct sequencing revealed that the, the FOXL2 gene affected individuals in the pedigree 1080-1096dup17 mutation. 4. Polyacrylamide electrophoresis validation results show that patients in the pedigree the FOXL2 gene CD and EF area as heterozygote. Conclusion 1. The full genome sequence with the GenBank database of the normal individual FOXL2 consistent BPES pedigree patients the FOXL2 gene primers CD PCR amplification product sequencing results show that patients 1080-1096dup17 duplication mutation. Causing the diseased individuals in the pedigrees showing BPES Ⅰ type phenotype. 2. BPES type I pedigree the 1080-1096dup17 found repeated mutations, cause after reading frame of 287 codons frameshift, leading to early termination of the encoded protein codon 361. Although this mutation did not affect the FOXL2 gene the forkhead region and polyalanine area, integrity, but will affect the tertiary structure of the protein, thus affecting the function of the protein. 3. In this study, first reported in the Chinese population in the 1080-1096dup17 repeat mutations, this mutation can occur in BPES familial or sporadic cases of the different races, so it may be a mutation originated independently and BPES illness a mutation hotspot of the individual, but also carry out important parts of BPES patients mutation analysis.

Mutation Analysis of Forkhead Transcriptional Factor 2 (FOXL2) in a Five-generation Chinese Family with BPES Type Ⅰ

Abstract

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