Premature Ovarian Failure, POF - FMR1

Premature Ovarian Failure, POF

Klinische Symptomatik

The unusually early onset of menopause (before the age of 40) is designated as premature ovarian failure (POF). POF is characterised by amenorrhea, reduced estrogen und increased gonadotropin levels. In 10-15% of affected women, the cause is an expansion of a trinucleotide repeat in the FMR1 gene. Detection of an expanded trinucleotide repeat in the FMR1 gene explains the cause of POF and provides information regarding relatives who may be affected by FMR1 associated diseases. These are:

• Fragile X Syndrome (FraX)
• Fragile X associated Tremor Ataxia Syndrome (FXTAS)
• Psychological problems, especially compulsive disorders and psychoses

Genetik

FMR1-associated disorders such as premature ovarian failure (POF) are X chromosomal inherited. They are caused by expanded CGG repeats in exon 1 of the FMR1 gene (fragile x mental retardation 1) on the long arm of chromosome X (Xq27.3). Regarding the repeat number normal, intermediate/gray zone, premutation and full mutation alleles are distinguished (see table).

The repetitive CGG trinucleotide repeat in exon 1 of the FMR1 gene is stable up to 40 repeats. When the number of repeats exceeds 40, the germ cell sequence becomes increasingly unstable (gray zone), which may result in a further expansion. A number of repeats in excess of 55 trinucleotides is designated a premutation. An aberrant hypermethylation of the promoter region normally occurs when the number of repeats exceeds 200 trinucleotides. This results in a loss of FMR1expression; this is referred to as a full mutation (s. Fragile X syndrome).

There is a high risk of expansion of maternal premutation alleles to full mutation upon transmission to offspring. Female premutation carriers have a 50% risk of transmitting an abnormal (premutation or full mutation) allele in each pregnancy. Risk for expansion of a maternal premutation to full mutation depends on repeat number.

Premutations cause an increased risk for FMR1-associated disorders such as premature ovarian failure (POF) and/or Fragile X Related Tremor/Ataxia Syndrome (FXTAS) . An increase in transcription is detectable from upper normal repeats onwards to the premutation region. Probably increased FMR1-mRNA has a toxic effect. The risk that a female premutation carrier will develop POF is indicated to be approximately 20%. A relation for female carriers of upper normal and gray zone alleles (35-55 CGG) for POF has not been proven. Increased risk for POF is discussed controversially in literature.

In addition to the risk of a woman with a FMR1 premutation of developing POF, there is first and foremost the risk that she will give birth to a child with fragile X syndrome. The risk of a full mutation increases commensurate to the number of the mother's CGG triplet repeats.

	CGG-Repeats	Male	Female
Normal allele	5 - 40	stable in individual and stable upon transmission
Grey Zone or Intermediate Allele	41 - 55	stable in individual and unstable upon transmission, however no expansion to full mutation in one generation
Premutation Allele	56 - 200	upon transmission: daughters are obligate carriers of a premutation; increased risk of FXTAS	transmission risk for full mutation in offspring depending on the repeat number; risk for expansion to full mutation when transmitted to offspring: 55-69: 3-5% 70-79: 31% 80-89: 58% 90-99: 80% 100-200: 94-100% increased risk of POF and FXTAS
Full Mutation Allele	> 200	Fragile X Syndrome, unstable in individual (mosaicism) and unstable upon transmission: daughters are obligate carriers of a premutation	approx. 60% of cases clinical manifestation of fragile X syndrome; unstable in individual (mosaicism) and unstable upon transmission: max. 50% risk of having children with a full mutation

additional genes are known to cause POF in rare cases:

• SF1, 11q13
• FSHR, 2p16
• BMP15/GDF9B, Xp11.2
• DIAPH2, Xq21.31
• FOXL2, 3q23
• LHCGR, 2p21
• AFF2, Xq28

Häufigkeit

Premutation alleles

• 1:200-1:300 in females

 

Diagnostik