In days of old _ that is, before movies, television and tourist safaris_ traveling circuses used to exhibit "human freaks of nature."
These side shows featured such aberrant phenotypes as Siamesetwins, giants, midgets, bearded ladies, "the alligator man." Today,geneticists recognize these anomalies, in the order named, asgestational non-disjunction, (conjoined siblings), Cushing's disease(a pituitary gland malignancy causing gigantism), achondroplasia(causing dwarfism), inappropriate testosterone secretion (hirsutism)and hereditary ichthyosis (scaly skin).
Lamellar ichthyosis (one of the disorder's most severe forms) is arare but serious affliction, in which the skin "resembles cracks in adry riverbed," said dermatologist John DiGiovanna, who headsclinical dermatological research at the National Institute of Arthritisand Musculoskeletal and Skin Diseases, (NIAMS) in Bethesda, Md.
It's caused, he explained, by a mutation in the gene that encodeskeratinocyte transglutaminase I. "It seems to eliminate that enzyme'sactivity," DiGiovanna told BioWorld Today, and added:"Transglutaminase is important in making crosslinks of smallproteins to form the cornified [horny] envelope of fully differentiatedepithelial cells in the skin. This, we believe, leads to the developmentof an abnormal stratum corneum, and therefore the scaling in theabnormal barrier in lamellar ichthyosis [LI].
"In this disease," he continued, "the individual corneocytes don'tcome apart normally. As a result, there are very large, oftenbrownish, plate-like scales all over the body. In some areas, such asthe legs, they can reach several centimeters in size, with fissuredareas around them. And the skin everywhere becomes very tight andtaut, to the point where eyelids can curl outward, for example."
LI, DiGiovanna said, is a recessive genetic disease in which it takes amutant gene in both parents to produce the affliction in theiroffspring.
Last week in San Francisco, at the 46th annual meeting of theAmerican Society of Human Genetics, he and his colleagues reportedlinkage analysis in the group of congenital recessive ichthyoses (towhich the lamellar form belongs), by which they mapped that LIversion to the long arm of human chromosome 14.
At the same time, the November issue of Nature Medicine appearedwith a paper titled "Corrective gene transfer in the human skindisorder lamellar ichthyosis." This first-ever application of genetherapy to a skin disease involved a transcontinental collaborationbetween researchers at Stanford and Harvard Universities.
Molecular biologist Jeffrey Morgan of Harvard Medical School is aco-author of the article. "What we did," he told BioWorld Today,"was take the normal human gene for transglutaminase, insert it into aretroviral vector, and transfer that correct copy into epidermalkeratinocyte cells from patients with severe lamellar ichthyosis. Wethen transplanted the gene therapy package into the skins of nudemice. What the study showed," Morgan said, "was that what wouldnormally be diseased skin is now normal."
That is, it restored cutaneous barrier functions to levels seen inepidermis regenerated by keratinocytes from patients with normalskin. Conversely, when the scientists grafted uncorrected cells fromLI patients onto the mice, the scaling and functional defects of thedisease were also reproduced.
Morgan's laboratory at the Shriners Burns Research Institute inCambridge, Mass., which is affiliated with Harvard, developed themouse model for transplanting the cultured keratinocytes. AtStanford, dermatologist Paul Khavarti and his team had culturedthese cells and made the vector with the normal gene.
Alfred Lane, who chairs dermatology at Stanford, observed, "This, tomy knowledge, is the first time anyone has successfully corrected agenetic defect in skin, albeit in a laboratory setting. Our goal is to beable to do corrective gene therapy on actual patients with skindiseases, within two to three years."
Morgan suggested that a suitable candidate for such an initial clinicalattempt might be epidermolysis bullosa, "a very disfiguring, skin-blistering and lethal" variant of ichthyosis.
The lamellar form, though not life-threatening, is life-devastating,physically and psychologically, to its victims and their families, asthe Foundation for Ichthyosis and Related Skin Types in Ardmore,Pa., vividly describes. It cites 1990 figures listing 3.3 cases of LI permillion Americans. With a nationwide 1990 total populationestimated at 250 million, this works out at 825 cases, plus an averageof 13 new births per year since.
Besides no cure, even palliative treatments for LI have toxic sideeffects, the Foundation pointed out, which can produce heightenedsusceptibility to coronary artery and degenerative bone diseases,among other risks. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.