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Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression.

ABSTRACT: The fragile X syndrome is due to the new class of dynamic mutations. It is associated with an expansion of a trinucleotide repeat (CGG) in exon 1 of the fragile X mental retardation gene 1 gene (FMR1). Here we present a fragile X family with an unique female patient who was rendered hemizygous for the FRAXA locus due to a large deletion of one X chromosome. In addition, the other X had a microdeletion in FMR1. PCR and sequence analysis revealed that the microdeletion included all CGG repeats plus 97 bp of flanking sequences, leaving transcription start site and translation start site intact. Despite this total lack of CGG repeats in the FMR1 gene, Western blot analysis showed expression of FMRP, and the patient's phenotype was essentially normal. X-inactivation studies of the androgen-receptor (AR) locus and haplotype determination of microsatellite markers gave evidence that the deletion probably originated from regression of a fully mutated FMR1 gene. Although the minimal number of CGG repeats hitherto reported in FRAXA is six, and at least four other genes associated with CGG repeats are known, suggesting an as yet unknown function of these repeats, our study clearly demonstrates that the absence of CGG repeats does not abolish expression of the FMR1 gene in lymphoblastoid cells.

SUBMITTER: Gronskov K

PROVIDER: S-EPMC1716002 | biostudies-other | 1997 Oct

REPOSITORIES: biostudies-other

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Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression.

Grønskov K K Hjalgrim H H Bjerager M O MO Brøndum-Nielsen K K

American journal of human genetics 19971001 4

The fragile X syndrome is due to the new class of dynamic mutations. It is associated with an expansion of a trinucleotide repeat (CGG) in exon 1 of the fragile X mental retardation gene 1 gene (FMR1). Here we present a fragile X family with an unique female patient who was rendered hemizygous for the FRAXA locus due to a large deletion of one X chromosome. In addition, the other X had a microdeletion in FMR1. PCR and sequence analysis revealed that the microdeletion included all CGG repeats plu ...[more]

PMID: 9382110

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Project description:Low FMR1 variants (CGGn<26) have been associated with premature ovarian aging, female infertility and poor IVF treatment success. Until now, there is little published information concerning possible molecular mechanisms for this effect. We wished to examine whether relative expression of RNA and the FMR1 gene's fragile X mental retardation protein (FMRP) RNA isoforms differ in women with various FMR1 sub-genotypes (normal, low CGGn<26 and/or high CGGn≥34). This prospective cohort study was conducted between 2014 and 2017 in a clinical research unit of the Center for Human Reproduction in New York City. The study involved a total of 98 study subjects, including 18 young oocyte donors and 80 older infertility patients undergoing routine in vitro fertilization (IVF) cycles. The main outcome measure was RNA expression in human luteinized granulosa cells of 5 groups of FMRP isoforms. The relative expression of FMR1 RNA in human luteinized granulosa cells was measured by real-time PCR and a possible association with CGGn was explored. All 5 groups of FMRP RNA isoforms examined were found to be differentially expressed in human luteinized granulosa cells. The relative expression of four FMR1 RNA isoforms showed significant differences among 6 FMR1 sub-genotypes. Women with at least one low allele expressed significantly lower levels of all 5 sets of FRMP isoforms in comparison to the non-low group. While it would be of interest to see whether FMRP is also decreased in the low-group we recognize that in recent years it has been increasingly documented that information flow of genetics may be regulated by non-coding RNA, that is, without translation to a protein product. We, thus, conclude that various CGG expansions of FMR1 allele may lead to changes of RNA levels and ratios of distinct FMRP RNA isoforms, which could regulate the translation and/or cellular localization of FMRP, affect the expression of steroidogenic enzymes and hormonal receptors, or act in some other epigenetic process and therefore result in the ovarian dysfunction in infertility.

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Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression.

Publications

Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression.

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