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Exome Sequencing Studies Link Variants in Genes Encoding Meiosis-related Proteins to Infertility

NEW YORK (GenomeWeb News) – Some cases of premature ovarian failure and related infertility may be due to mutations affecting proteins involved in meiosis, according to a pair of exome sequencing reports published in the New England Journal of Medicine yesterday.

Researchers led by Eric Vilain, a professor of human genetics, pediatrics, and urology at the University of California, Los Angeles, performed exome sequencing on a set of sisters belonging to a Palestinian family with a history of premature ovarian failure to home in on a deletion in the STAG3 gene, which encodes a subunit of the cohesin ring that regulates the interaction of sister chromatids during meiosis. In mice, the researchers said in NEJM, disruption of the STAG3 gene leads to sterility and oocyte arrest. It may also affect fertility in men as it does in male mice, they said, but further studies need to be done to confirm that.

"Our work enables us to causally relate mutations in a gene of the cohesin complex with human infertility," co-author Alberto Pendás, a researcher with the Spanish National Research Council, said in a statement. "It also demonstrates for the first time in humans that POF and azoospermia, a disorder that impedes normal sperm production, are probably the two faces of the same genetic disease."

Separately, Fudan University's Bai-Lin Wu and colleagues turned to exome sequencing of two Chinese sisters with primary ovarian insufficiency to narrow in on a compound heterozygous mutation in HFM1, which encodes a protein that, in mice, allows homologous recombination of chromosomes during meiosis, as they also wrote in NEJM.

Premature ovarian failure, or primary ovarian insufficiency, in which a woman's ovaries stop working normally before she reaches the age of 40, affects about 1 percent of women, and is one possible cause of female infertility. In about 10 percent to 15 percent of cases, there is an underlying genetic cause of the disorder, and while a number of regions have been linked to the disorder, the cause of most cases is unknown.

Vilain and colleagues sequenced the whole exomes of two sisters, one affected and one unaffected, belonging to a consanguineous Palestinian family with multiple cases of premature ovarian failure. In the fourth generation of the family, for instance, four of the six sisters were affected; one sister experienced premature ovarian failure at 19 and was also diagnosed with ovarian cancer. Previous genetic testing ruled out known genetic causes of the disorder in the family.

Samples from the two sisters were sequenced on the Illumina HiSeq 2000 platform after whole-exome capture on the Agilent SureSelectXT 50 Mb Exon Capture array. The researchers generated some 3.3 billion reads per sample, which covered about 93 percent of the targeted sequences at a 10x or greater level.

After filtering those reads, the researchers uncovered a deletion in the STAG3 gene that was homozygous in the affected sibling and heterozygous in the unaffected one.

The researchers confirmed the segregation of the variant using Sanger sequencing of the unaffected parents, affected sisters, and unaffected brothers and sisters. All four sisters with premature ovarian failure were homozygous for the deletion, while the unaffected family members were either heterozygous or homozygous for the nonmutant allele.

STAG3 encodes a cohesin protein, and the deletion, the researchers said, leads to a frameshift mutation, a premature stop codon, and a truncated protein that lacks the armadillo domain that is predicted to interact with other proteins or with nucleic acids.

In a STAG3 mutant mouse model of the disorder, Vilain and colleagues found that oocytes from the mutant mice did not progress beyond the leptotene stage of meiosis. Additionally, they uncovered evidence suggesting that STAG3 is essential for the proper formation of the cohesin ring and synaptonemal complex as well as for maintaining sister chromatid cohesion in mammalian oocytes during meiosis.

Since STAG3 appears to be to be essential for meiosis, Vilain and colleagues hypothesized that a homozygous defect in it would affect the fertility of both men and women. In this family, though, the two brothers were heterozygous for the deletion. In mice, the researchers noted, male homozygous mutants were infertile.

"Now, the analysis of this STAG3-deficient mouse has enabled us to corroborate that is a cause of female sterility and a very strong candidate for male infertility," Pendás added.

Meanwhile, Fudan's Wu and colleagues uncovered a role for a separate meiosis-related protein in premature ovarian failure, as they detailed in a letter in NEJM.

By sequencing the whole exome of two Chinese sisters with premature ovarian failure and their parents, the researchers narrowed in on a compound heterozygous mutation that the sisters shared affecting the HFM1 gene. The parents had one copy each and had normal fertility.

They screened an additional cohort of nearly 70 Chinese women with sporadic premature ovarian failure and found another compound heterozygous mutation affecting HFM1. Those variants were not found in 316 controls matched for ethnicity, gender, and age, nor in the 1,000 Genomes Project or Exome Sequencing Project datasets, the researchers noted.

HFM1, the researchers said, encodes a protein involved with homologous recombination in mice, and mice lacking HFM1 are infertile.

"We suggest that mutations in genes encoding proteins that regulate meiosis can result in autosomal recessive primary ovarian insufficiency in humans," Wu and colleagues said.

In addition, genes involved in crucial developmental processes like STAG3, Vilain and colleagues noted, have been linked to cancer. A paralog of STAG3, they added, is thought to be a driver mutation of acute myeloid leukemias and loss of heterozygosity of STAG3 occurs in epithelial ovarian carcinomas

In the Palestinian family, they pointed out, the sister who was 19 at the time of premature ovarian failure also had bilateral ovarian cancer.

"The germinal origin of these tumors suggests a possible role for the germline STAG3 truncating mutation in genomic instability in the few oocytes that survived ovarian degeneration," Vilain and colleagues said. "Accordingly, it would be interesting to investigate whether women carrying STAG3 mutations resulting in premature ovarian failure have an increased risk of germ-cell tumors."

The researchers noted that the role of STAG3 in premature ovarian failure suggests that variants in related genes could also be involved. "We propose that mutations affecting other meiosis-specific subunits of the cohesin complex could lead to similar functional defects and explain ovarian failure in women with premature ovarian failure," Vilain and colleagues added.

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