Science Vol. 275 14 March 1997

HOX Gene Links Limb, Genital Defects

Ever since they were shown to be conserved between vertebrates and arthropods in 1984, the large family of so-called HOX genes has provided a master key to unlocking the intricacies of development. Originally found in the fruit fly Drosophila melanogaster , where they help lay down the insect's head-to-tail pattern, HOX genes were soon shown to be crucial for the development of animal species ranging from lowly nematodes to mammals.

But the elucidation of the role of HOX genes has lagged in one important organism: humans. Although developmental biologists think these genes are important in humans - after all, each of us carries 39 of them arranged in four roughly parallel sets - the only way to know for sure is to find HOX mutations in people and see what kind of abnormalities they cause. But such human mutations have proved scarce, possibly because the genes are so important that many mutations prove fatal. The first such mutation, which causes abnormal hands and feet, was discovered only last year. Now, University of Michigan pediatric geneticist Jeffrey Innis and graduate student Douglas Mortlock have uncovered a second window into human HOX gene function, a mutation that causes genital, as well as limb, abnormalities.

Foxy feet and fingers. HOX gene mutation causes shorter thumbs shifted down the hand, and similar abnormalities in big toes.

Developmental biologists are pleased by the finding, described in last month's issue of Nature Genetics, because it ties in with previous work showing that inactivation of the comparable gene in mice causes similar defects. "This report is tremendous because it demonstrates that what we've seen in mice is valid for humans," says HOX gene expert Denis Duboule of the University of Geneva "This has profound evolutionary implications." The link between limbs and genitals may help explain why even apparently nonvital HOX genes - and the parts of the body plan they govern - are so strongly conserved in evolution, he says.

The work began when Mortlock and Innis identified and published a mutation causing limb and genital anomalies in the mouse hoxa13 gene last year. Then, a colleague alerted them to the presence of similar malformations in a Michigan family. The family's hereditary abnormalities included thumbs and big toes that are both shorter than normal and shifted slightly toward the elbow and knee. The limb anomalies do not cause any apparent hardship to family members, who refer to their differences as "foxy feet" and "butterfly fingers." But three women in the family also have uterine abnormalities that led one to be infertile and the others to have difficulty conceiving. Mortlock and Innis sampled the family's DNA and found that they indeed carried a mutation in the human form of the HOXA13 gene.

On closer study of the mutated gene, Mortlock and Innis found that one of its codons for the amino acid tryptophan was replaced by a stop codon. So the HOXA13 protein is incomplete, missing 20 amino acids. This may eliminate or reduce the protein's ability to bind to DNA, presumably altering the transcription of target genes and so somehow altering morphology, says Innis.

A link between a HOX gene mutation and both limb and genital abnormalities had already shown up in mice several years ago. Duboule's team had inactivated the closely related gene, hoxdl3, in mice and found that the animals had smaller digits and many males had malformed penises. Then last year, a team led by cell biologist Bjorn Olsen of Harvard Medical School found that mutations in the HOXD13 gene in a human family led to limb defects - but the researchers did not report whether family members had genital defects (Science , 26 April 1996, p. 548).

Now that the limb-genital link has shown up in a different human HOX gene, Duboule says, it may explain why even nonvital HOX genes appear to be conserved across evolutionary history. Mutations in genes needed for normal genital development wouldn't be tolerated because they lessen the likelihood that mutated individuals could reproduce. Duboule speculates that this link may even help explain one of life's great mysteries: why so many vertebrates have five digits on their hands and feet - a number that has been favored for over 300 million years of evolution notes paleontologist Michael Coates of University College, London.

The HOX genes play a pivotal if poorly understood role in determining the number of digits, and if they are needed in reproductive function, then conservation of the digit number may have been secondary to that, an idea that gets cautious support from Innis and Coates. Put simply, says Coates, "stability in the distal part of the limb is favored because otherwise you mess up the genitalia. That's a very nice argument," which "appears to be strengthened by the new findings."

There's little proof yet, however, that HOX genes owe their stability to the genital connection. Answers may have to wait for more details on genes activated by the HOX genes and how they alter the body plan. Despite the new human family and the ongoing work in mice, "we still don't know what these genes are actually doing," says Duboule. "It's remarkably mysterious."

- Steven Dickman

Steven Dickman is a science writer in Cambridge, Massachusetts.

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