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A new Tel Aviv University study throws a spotlight on a previously unidentified cause of POI — Primary Ovarian Insufficiency — a unique mutation in a gene called SYCE1 not previously associated with POI in humans.
Genetic mutation cause of ovarian failure
Tel Aviv University researchers discover unique genetic disorder responsible for ovarian insufficiency in women under 40.
Premature ovarian failure, also called: primary ovarian insufficiency (POI), affects 1% of all women worldwide. It is often associated with infertility, however, the exact cause of the condition is difficult to determine.
A new Tel Aviv University study throws a spotlight on a previously-unidentified cause of POI: a unique mutation in a gene called SYCE1 not previously associated with POI in humans.
The research was led by Dr. Liat de Vries and Proffessor Lina Basel-Vanagaite of TAU's Sackler Faculty of Medicine and Schneider Children's Medical Center and conducted by a team of researchers from both TAU and Schneider. The work is published in the Journal of Clinical Endocrinology and Metabolism,
While the genes involved in chromosome duplication and division had been shown to cause POI in animal models, this is the first time a similar mutation has been identified in humans.
"Researchers believe that POI may be associated with Turner's syndrome, a condition in which a woman has only one X chromosome instead of two, or could be due to toxins like chemotherapy and radiation therapy. However, in 90% of the cases, the exact cause remains a mystery."
Liat de Vries PhD, Sackler Faculty of Medicine and Schneider Children's Medical Center
The idea for the study surfaced when Dr. de Vries was asked to treat two POI patients, daughters of two sets of Israeli-Arab parents who were related to each other. The girls presented with typical POI symptoms: one had the appearance of puberty but had not gotten her period, and the other one had not started puberty at all. After ruling out the usual suspects (toxins, autoimmune disease, and known chromosomal and genetic diseases), the researchers set out to identify the genetic cause of POI in the two young women.
Dr. de Vries: "One of my main topics of interest is puberty. The clinical presentation of the two sisters, out of 11 children of first-degree cousins, was interesting. In each of the girls, POI was expressed differently. One had reached puberty and was almost fully developed but didn't have menses. The second, 16 years old, showed no signs of development whatsoever."
The researchers performed genotyping in the patients, their parents, and siblings. For this, DNA from the affected sisters was subjected to whole-exome sequencing. Genotyping was also performed in 90 ethnically matched control individuals.
Genotyping revealed a mutation that results in nonfunctional protein product in the SYCE1 gene in both affected sisters. The parents and three brothers were found to be carriers of the mutation, and an unaffected sister did not carry the mutation.
"By identifying the genetic mutation, we saved the family a lot of heartache by presenting evidence that any chance of inducing fertility in these two girls is slight," said Dr. de Vries. "As bad as the news is, at least they will not spend years on fertility treatments and will instead invest efforts in acquiring an egg donation, for example. Knowledge is half the battle -- and now the entire family knows it should undergo genetic testing for this mutation."
The researchers are currently investigating evidence of the effects of this genetic mutation on male members of the family. "We are trying to get more family members tested, but it is not always easy in traditional societies. There is still a lot to be done on this subject," said Dr. de Vries.
Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early menopause. Genes involved in essential steps in chromosome synapsis and recombination during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been shown to cause POI in animal models. We describe for the first time a homozygous mutation in SYCE1 in humans.
To identify the genetic cause of POI in an Israeli Arab family with a consanguineous pedigree.
DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of the additional family members were determined by Sanger sequencing. Genotyping was also performed in 90 ethnically matched control individuals.
A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation. The mutation was not identified in the DNA samples from the 90 control subjects.
Given the known function of the SYCE1 gene, we suggest that the nonsense mutation identified accounts for the POI phenotype. These results highlight the importance of the synaptonemal complex and meiosis in ovarian function.
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