RECEPTOR MUTATION EXPLAINS WHY SOMEBOYS ARE BORN WITH A UTERUS
By David N. LeffScience Editor
Unless a gender-ambivalent embryo takes timelycountermeasures, its Mllerian ducts will develop into auterus and Fallopian tubes. If testosterone and anti-Mllerian hormone (AMH) kick in, sometime after thefourth week of gestation, those female-fashioning ductswill regress, letting maleness take over.
Sometimes this sex-specifying system stumbles. AMH iseither defective or fails to bind its receptor target, so aboy-baby is born with hidden, vestigial girl-baby tissuesin its body.
French pediatric endocrinologist Nathali Josso toldBioWorld Today what can happen:
"The child is born a normal male, but he has eithercryptorchidism _ 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 thesurgeon finds that either the testes are not descended,because a Fallopian tube holds them back, or _ if he'soperating on an inguinal hernia _ the herniated tissue isnot of the gut, as he expected, but it's a uterus andFallopian 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 spermcells, and male infertility."
This condition, persistent Mllerian duct syndrome(PMDS) "is not as rare as the textbooks say," Jossopointed out. Her laboratory of reproductive endocrinologyat the INSERM (National Institute of Medical ScienceResearch) unit in Montrouge, France receives DNAsamples from PMDS patients the world over for ductanalysis.
"We are getting about 15 samples of DNA a year frompatients, so we think the condition is not as abnormal as itwas supposed to be," Josso observed.
She and molecular geneticist Jean-Yves Picard areprincipal co-authors of a research article in the Decemberissue of Nature Genetics. So is Richard Cate, groupleader of molecular genetics at Biogen Inc., inCambridge, Mass.
Their paper is titled: "Insensitivity to anti-Mllerianhormone due to a mutation in the human anti-Mllerianhormone receptor." It reports, Josso said, "the first humanmutation of a receptor for a member of the transforminggrowth factor-beta (TGF-b) receptor gene family,"namely, that for AMH.
Their patient in question was a three-month-old boy withan undescended right testicle and suspected left inguinalhernia. "At surgery," the paper reported, "both testes werefound in the left scrotum and inguinal canal, associatedwith a uterus and two Fallopian tubes."
The French team co-cultured a small testicular fragmentwith fetal rat Mllerian ducts. It elicited normal ductregression, confirming that the child could secretefunctional anti-Mllerian hormone.
Ergo, the abnormality lay in one or both of the hormone'sreceptors. As Biogen's Cate told BioWorld Today, "Wefound a splicing mutation in the hormone's type IIreceptor, which generated abnormal messenger RNAs."
"The importance of our paper," Josso said, "is that somepeople, particularly in the U.S., are not convinced that thereceptor we have cloned is really the anti-Mllerian typeII receptor. So by showing that a mutation in this geneproduced the persistent Mllerian duct syndrome, itshows that we have really cloned the right gene."
Cate concurred. "One of the key reasons for cloning it atthe time," he said, "was to confirm that it was indeed thereceptor for MIS, that is to say, AMH. This providedabsolute genetic proof that it was." The Biogen scientistpointed 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 inboth genes that encode his Mllerian Inhibiting Substancereceptor. He inherited one bad allele from his mother andone from his father. Both have the identical mutation. Hewas unlucky."
He added "Another point of academic interest: This is thefirst member of the TGF-b receptor family in which wefound 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, "whetherAMH has a specific type I receptor of its own _ whichwe're trying to clone _ or whether it signals through thetype I receptor of other members of the TGF-b family."
At the same time, she and her colleagues are "trying tocharacterize the 15 new receptor mutations we've foundsince reporting the first one in the current NatureGenetics."
Cate cites "One more reason we're interested in this:Once we had the mutant receptor, we could ask whethercells that carry it are involved in any diseases. Forinstance, whether tumors have the Mllerian InhibitingSubstance receptor, and if they did, whether we can usethat as a possible way of targeting these tumor cells."
He concluded: "At this point, we have found the receptoron only a couple of ovarian tumors. We're hoping thatwhen people see this paper, they may look for it on othertumors." n
(c) 1997 American Health Consultants. All rights reserved.