Genetic mutations may be linked to infertility, early menopause
Gene in fruit flies, worms, zebrafish, mice and people may help explain
some fertility issues

Date:
August 31, 2020
Source:
Washington University School of Medicine
Summary:
A new study identifies a specific gene's previously unknown role in
fertility. When the gene is missing in fruit flies, roundworms,
zebrafish and mice, the animals are infertile or lose their
fertility unusually early but appear otherwise healthy. Analyzing
genetic data in people, the researchers found an association
between mutations in this gene and early menopause.



FULL STORY ==========================================================================
A new study from Washington University School of Medicine in St. Louis identifies a specific gene's previously unknown role in fertility. When
the gene is missing in fruit flies, roundworms, zebrafish and mice,
the animals are infertile or lose their fertility unusually early but
appear otherwise healthy.

Analyzing genetic data in people, the researchers found an association
between mutations in this gene and early menopause.


==========================================================================
The study appears Aug. 28 in the journal Science Advances.

The human gene -- called nuclear envelope membrane protein 1 (NEMP1) --
is not widely studied. In animals, mutations in the equivalent gene had
been linked to impaired eye development in frogs.

The researchers who made the new discovery were not trying to study
fertility at all. Rather, they were using genetic techniques to find
genes involved with eye development in the early embryos of fruit flies.

"We blocked some gene expression in fruit flies but found that their eyes
were fine," said senior author Helen McNeill, PhD, the Larry J. Shapiro
and Carol- Ann Uetake-Shapiro Professor and a BJC Investigator at the
School of Medicine.

"So, we started trying to figure out what other problems these animals
might have. They appeared healthy, but to our surprise, it turned out
they were completely sterile. We found they had substantially defective reproductive organs." Though it varied a bit by species, males and
females both had fertility problems when missing this gene. And in
females, the researchers found that the envelope that contains the
egg's nucleus -- the vital compartment that holds half of an organism's chromosomes -- looked like a floppy balloon.



========================================================================== "This gene is expressed throughout the body, but we didn't see this floppy balloon structure in the nuclei of any other cells," said McNeill, also
a professor of developmental biology. "That was a hint we'd stumbled
across a gene that has a specific role in fertility. We saw the impact
first in flies, but we knew the proteins are shared across species. With
a group of wonderful collaborators, we also knocked this gene out in
worms, zebrafish and mice. It's so exciting to see that this protein
that is present in many cells throughout the body has such a specific
role in fertility. It's not a huge leap to suspect it has a role in
people as well." To study this floppy balloon-like nuclear envelope,
the researchers used a technique called atomic force microscopy to poke
a needle into the cells, first penetrating the outer membrane and then
the nucleus's membrane. The amount of force required to penetrate the
membranes gives scientists a measure of their stiffness. While the outer membrane was of normal stiffness, the nucleus's membrane was much softer.

"It's interesting to ask whether stiffness of the nuclear envelope of
the egg is also important for fertility in people," McNeill said. "We
know there are variants in this gene associated with early menopause. And
when we studied this defect in mice, we see that their ovaries have lost
the pool of egg cells that they're born with, which determines fertility
over the lifespan. So, this finding provides a potential explanation for
why women with mutations in this gene might have early menopause. When
you lose your stock of eggs, you go into menopause." McNeill and her colleagues suspect that the nuclear envelope has to find a balance between being pliant enough to allow the chromosomes to align as they should for reproductive purposes but stiff enough to protect them from the ovary's stressful environment. With age, ovaries develop strands of collagen with potential to create mechanical stress not present in embryonic ovaries.

"If you have a softer nucleus, maybe it can't handle that environment,"
McNeill said. "This could be the cue that triggers the death of eggs. We
don't know yet, but we're planning studies to address this question."
Over the course of these studies, McNeill said they found only one other problem with the mice missing this specific gene: They were anemic,
meaning they lacked red blood cells.

"Normal adult red blood cells lack a nucleus," McNeill said. "There's
a stage when the nuclear envelope has to condense and get expelled
from the young red blood cell as it develops in the bone marrow. The
red blood cells in these mice aren't doing this properly and die at
this stage. With a floppy nuclear envelope, we think young red blood
cells are not surviving in another mechanically stressful situation."
The researchers would like to investigate whether women with fertility
problems have mutations in NEMP1. To help establish whether such a link
is causal, they have developed human embryonic stem cells that, using
CRISPR gene-editing technology, were given specific mutations in NEMP1
listed in genetic databases as associated with infertility.

"We can direct these stem cells to become eggs and see what effect
these mutations have on the nuclear envelope," McNeill said. "It's
possible there are perfectly healthy women walking around who lack the
NEMP protein. If this proves to cause infertility, at the very least
this knowledge could offer an explanation. If it turns out that women
who lack NEMP are infertile, more research must be done before we could
start asking if there are ways to fix these mutations -- restore NEMP, for example, or find some other way to support nuclear envelope stiffness."

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yonit Tsatskis, Robyn Rosenfeld, Joel D. Pearson, Curtis Boswell,
Yi Qu,
Kyunga Kim, Lacramioara Fabian, Ariz Mohammad, Xian Wang, Michael I.

Robson, Karen Krchma, Jun Wu, Joa~o Gonc,alves, Didier Hodzic, Shu
Wu, Daniel Potter, Laurence Pelletier, Wade H. Dunham, Anne-Claude
Gingras, Yu Sun, Jin Meng, Dorothea Godt, Tim Schedl, Brian Ciruna,
Kyunghee Choi, John R. B. Perry, Rod Bremner, Eric C. Schirmer,
Julie A. Brill, Andrea Jurisicova, Helen McNeill. The NEMP family
supports metazoan fertility and nuclear envelope stiffness. Science
Advances, 2020; 6 (35): eabb4591 DOI: 10.1126/sciadv.abb4591 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200831154401.htm

--- up 1 week, 6 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)