RECEPTOR MUTATION EXPLAINS WHY SOME BOYS ARE BORN WITH A UTERUS

By David N. Leff Science Editor

Unless a gender-ambivalent embryo takes timely countermeasures, its Mllerian ducts will develop into a uterus and Fallopian tubes. If testosterone and anti- Mllerian hormone (AMH) kick in, sometime after the fourth week of gestation, those female-fashioning ducts will regress, letting maleness take over.

Sometimes this sex-specifying system stumbles. AMH is either defective or fails to bind its receptor target, so a boy-baby is born with hidden, vestigial girl-baby tissues in its body.

French pediatric endocrinologist Nathali Josso told BioWorld Today what can happen:

"The child is born a normal male, but he has either cryptorchidism _ one or both testes are not descended _ or what appears to be an inguinal [i.e., groin-region] hernia.

"So the patient is brought to surgery," Josso continued, "nowadays usually within the first year of life. There the surgeon finds that either the testes are not descended, because a Fallopian tube holds them back, or _ if he's operating on an inguinal hernia _ the herniated tissue is not of the gut, as he expected, but it's a uterus and Fallopian tube."

Unless the surgeon removes these aberrant female tissues, Josso explained, "the testes will not be able to descend; the cryptorchidism can lead to degeneration of the sperm cells, and male infertility."

This condition, persistent Mllerian duct syndrome (PMDS) "is not as rare as the textbooks say," Josso pointed out. Her laboratory of reproductive endocrinology at the INSERM (National Institute of Medical Science Research) unit in Montrouge, France receives DNA samples from PMDS patients the world over for duct analysis.

"We are getting about 15 samples of DNA a year from patients, so we think the condition is not as abnormal as it was supposed to be," Josso observed.

She and molecular geneticist Jean-Yves Picard are principal co-authors of a research article in the December issue of Nature Genetics. So is Richard Cate, group leader of molecular genetics at Biogen Inc., in Cambridge, Mass.

Their paper is titled: "Insensitivity to anti-Mllerian hormone due to a mutation in the human anti-Mllerian hormone receptor." It reports, Josso said, "the first human mutation of a receptor for a member of the transforming growth factor-beta (TGF-b) receptor gene family," namely, that for AMH.

Their patient in question was a three-month-old boy with an undescended right testicle and suspected left inguinal hernia. "At surgery," the paper reported, "both testes were found in the left scrotum and inguinal canal, associated with a uterus and two Fallopian tubes."

The French team co-cultured a small testicular fragment with fetal rat Mllerian ducts. It elicited normal duct regression, confirming that the child could secrete functional anti-Mllerian hormone.

Ergo, the abnormality lay in one or both of the hormone's receptors. As Biogen's Cate told BioWorld Today, "We found a splicing mutation in the hormone's type II receptor, which generated abnormal messenger RNAs."

"The importance of our paper," Josso said, "is that some people, particularly in the U.S., are not convinced that the receptor we have cloned is really the anti-Mllerian type II receptor. So by showing that a mutation in this gene produced the persistent Mllerian duct syndrome, it shows that we have really cloned the right gene."

Cate concurred. "One of the key reasons for cloning it at the time," he said, "was to confirm that it was indeed the receptor for MIS, that is to say, AMH. This provided absolute genetic proof that it was." The Biogen scientist pointed out that "in the U.S., what Europeans term AMA _ Anti-Mllerian Hormone _ is known as MIS _ Mllerian Inhibiting Substance."

He explained that "their PMDS patient has a mutation in both genes that encode his Mllerian Inhibiting Substance receptor. He inherited one bad allele from his mother and one from his father. Both have the identical mutation. He was unlucky."

He added "Another point of academic interest: This is the first member of the TGF-b receptor family in which we found a mutation in a human being."

Having cloned the human AMH's type II receptor, Josso's lab is now tackling the hormone's putative type I. "We don't know at this point," she explained, "whether AMH has a specific type I receptor of its own _ which we're trying to clone _ or whether it signals through the type I receptor of other members of the TGF-b family."

At the same time, she and her colleagues are "trying to characterize the 15 new receptor mutations we've found since reporting the first one in the current Nature Genetics."

Cate cites "One more reason we're interested in this: Once we had the mutant receptor, we could ask whether cells that carry it are involved in any diseases. For instance, whether tumors have the Mllerian Inhibiting Substance receptor, and if they did, whether we can use that as a possible way of targeting these tumor cells."

He concluded: "At this point, we have found the receptor on only a couple of ovarian tumors. We're hoping that when people see this paper, they may look for it on other tumors." n

(c) 1997 American Health Consultants. All rights reserved.