To say that males are merely failed females sounds very "politicallycorrect." In fact, the statement is genetically accurate.
Human embryos start their gestation under the developmentaldirection of the XX sex chromosome, whose genes dictatefemaleness. Along the way, in approximately half of all futurefetuses, the maleness Sry gene (short for "sex determining region, Ychromosome) kicks in, to override the XX budding femininegenotype, and impose Y-chromosome testes, penis and othermasculine attributes instead.
Sry's first switch-hit secretes a hormone that abrogates the Mullerianduct, thus preventing fallopian tubes and uterus from forming. Thenthe gene turns on testosterone, which forms the male's internalgenitalia. Sry is a member of the recently identified family of Soxgenes.
So what else is new? Specifically, another member of the Sry genefamily, Sox9, which in rare cases can reverse the sex of a fetus in themaking.
In mercifully rare instances, embryos already committed to thecontrol of the male-making Y chromosome suddenly flip over to thefemale persuasion, or vice versa . A defective SOX9 gene on humanchromosome 17 throws that sex-reversing switch.
This gender-defining reversion to type would be no tragedy, but theSox9 gene's concomitant effects are tragic. This DNA sequence sitson the long arm of chromosome 17, at the site of two loci. Onedecrees autosomal sex reversal; the other inflicts an unusual, butusually lethal, skeletal malformation called campomelic dysplasia(CD).
So far, 121 CD patients have been reported. As the January issue ofNature Genetics notes in an editorial, "Of the 50 or so reported CDcases that are chromosomally male, more than two-thirds arephenotypically female." The title of a paper in Nature for Dec. 8,1994, makes the connection: "Campomelic dysplasia and autosomalsex reversal caused by mutations in an SRY-related gene."
Infants born with CD rarely live longer than a few months -- and nowonder. Australian molecular biologist Peter Koopman, atQueensland University in Brisbane, isolated the Sry gene four yearsago. In the same current Nature Genetics, he describes the humanskeletal dismorphology syndrome (CD) caused by a mutated Sox9 hehas identified:
"Bowing and angulation of the long bones, unusually small scapulae[shoulder blades], deformed pelvis and spine, and a missing pair ofribs. Craniofacial defects such as cleft palate, micrognathia [smalljaws], flat face and hypertelorism [very widely spaced eyes] arecommon," as is mental retardation.
Koopman's paper, titled "The Sry-related gene Sox9 is expressedduring chondrogenesis in mouse embryos," explains the mutantgene's connection to embryonic skeletal formation as well as sexreversal. "Our results indicate," he reported, "that the primary defectin CD is skeletal dysgenesis and not vascular anomalies or generalhypoplasia, as has been proposed."
The cloning of Sox9, he foresees, "will allow new approaches to themolecular genetic analysis of skeletal development."
Molecular biologist Robert Dubin, in the human genetics division atNew York University Medical Center, is active in the current growthindustry of Sry research. "We've been trying to understand exactlywhat Sry does," Dubin told BioWorld Today. "We know that it'sdefinitely required for testis development. So is Sox9."
He added that its clinical potential in campomelic dysplasia is"definitely" here-and-now. "Now that it is known to be associatedwith a human genetic disease," Dubin observed, "you can do genetictesting on fetuses. For diagnostic testing," he surmised, "I'm sure it'sbeing done as we speak. And there's a potential for gene therapy." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.