Study identifies pathway required for
normal reproductive development
Gene defects cause infertility,
lack of sense of smell in humans and mice
BOSTON - October 15, 2007 - Massachusetts General Hospital
(MGH) clinical researchers, in collaboration with basic scientists
from the University of California,
Irvine, (UC Irvine) have identified a new molecular pathway
required for normal development of the reproductive, olfactory and
circadian systems in both humans and mice. In their report to appear
in the Proceedings of the National Academy of Sciences, the
team describes defects in a gene called PROK2 (prokineticin 2) in
human siblings with two different forms of infertility. The UC Irvine
team had previously reported that mice lacking PROK2 had abnormal
olfactory structures and disrupted circadian rhythm. The paper is
receiving early online release.
"We have demonstrated that PROK2 signaling is a novel pathway
that is critical to the development of neurons that control the
reproductive system, findings that should enable better understanding
of human reproduction," says lead author Nelly Pitteloud, MD,
of the Reproductive
Endocrine Unit in the MGH Department of Medicine.
The current study is the latest in a series of investigations by
the MGH group into the genetic basis of idiopathic hypogonadotropic
hypogonadism (IHH), a rare condition in which puberty does not take
place naturally. IHH occurs when a structure in the brain called
the hypothalamus fails to develop neurons that secrete gonadotropin-releasing
hormone (GnRH), a major controller of the reproductive system. Several
genes involved in IHH have been discovered by the MGH investigators
and others throughout the world; however, only 30 percent of IHH
cases can currently be attributed to a known gene defect.
The investigation focused on PROK2, a protein known to regulate
the development of the olfactory bulbs, the portion of the brain
involved in the sense of smell, and to have a critical role in circadian
rhythm in the mice. A form of IHH called Kallmann syndrome involves
lack of both reproductive development and a sense of smell. PROK2's
involvement in these systems led the researchers to investigate
the protein's potential role in GnRH deficiency in human and mice.
The MGH team analyzed the PROK2 genes of 100 study participants:
50 with Kallmann syndrome and 50 with IHH and a normal sense of
smell. Three members from the same family in Portugal - two brothers
and a sister - had identical defects in both copies of the PROK2
gene. Further study of this family revealed another brother with
the mutation in only one PROK2 copy and a normal reproductive history.
Five siblings of these individuals - now in their 70s - had died
in infancy; similar early deaths have been seen in the PROK2-deficient
mice. Interestingly, while the two affected brothers both had Kallmann
syndrome, their affected sister had a normal sense of smell but
did not experience normal puberty.
"Until recently, IHH with a normal sense of smell and Kallmann
syndrome with no sense of smell had been considered two distinct
clinical entities," says Pitteloud, an assistant professor
of Medicine at Harvard Medical School. "We now have described
several kindreds in which different family members exhibit both
syndromes yet harbor the identical mutation. So, it looks like additional
gene defects or environmental cues modify how these syndromes develop
in affected families."
The UC Irvine team was led by Qun-Yong Zhou, PhD, a professor of
Pharmacology in its School of Medicine. His group has made fundamental
contributions to the understanding of the neurobiological functions
of prokineticin and its receptors. Their analysis of the reproductive
status of mice lacking functional copies of Prok2 gene revealed
that the animals' reproductive defect is due to the abnormal migration
of neurons that secrete GnRH.
"Many recessive human genetic disorders, particularly the
ones that have associated infertility symptom, are very difficult
or almost infeasible to investigate using genetic analysis. The
current study provides an elegant example how mouse studies can
pinpoint the underlying genetic cause for human IHH disorders."
Zhou and William Crowley Jr, MD, chief of the MGH Reproductive
Endocrine Unit and director of the Harvard Reproductive Endocrine
Sciences Center, are senior authors of the PNAS paper. Other co-authors
are Taneli Raivio, Lindsay Cole, Lacey Plummer, and Elka Jacobson-Dickman,
of MGH; Cheng Kang Zhang and Jia-Da Li, UC Irvine; Duarte Pignatelli,
University of Porto, Portugal; and Patricia Mellon, University of
California at San Diego. The study was supported by grants from
the National Institutes of Health.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
The University of California, Irvine is a top-ranked university
dedicated to research, scholarship and community service. Founded
in 1965, UCI is among the fastest-growing University of California
campuses, with more than 25,000 undergraduate and graduate students
and about 1,800 faculty members. The second-largest employer in
dynamic Orange County, UCI contributes an annual economic impact
of $3.7 billion.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Tom Vasich, UC Irvine Public
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