By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-related research:
Loss of scalp hair, especially among men, is a socially and psychologically distressing syndrome that generates large markets in replacement implantation, wigs and, recently, topically applied hair-regrowing chemotherapeutics.
Total absence of all body hair -- alopecia universalis -- is a relatively rare, and poorly understood, inherited affliction. This whole-body baldness affects rats and mice as well as humans, which facilitated mapping its gene to the short arm of human chromosome 8.
The discovery is reported in the October 1998 issue of the British journal Human Molecular Genetics under the title "Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia."
The paper's co-authors, at the University of Bonn, in Germany, studied the complete lack of hair in two extended inbred families, one Pakistani, and the other Omani. They detected separate homozygous mutations of the gene (conferred by both parents) in both kindreds. Both mutations were absent in 384 Caucasian, 80 Omani and 52 Pakistani control chromosomes.
To pinpoint the genomic location of the human gene, the researchers proceeded by analogy to the mouse hairless gene, on murine chromosome 14. These bald rodents begin losing their hair about two weeks after birth, and shed their coats completely by three or four weeks of age.
The team sequenced the complete coding region from genomic DNA of two affected Pakistani and two Omani probands, plus one unaffected Caucasian individual recruited from their laboratory staff. Scalp biopsy from one Omani subject showed no hair follicles at all, whereas empty follicles existed on the scalp of a Pakistani subject. This apparently reflects the relative severity of the two nucleotide mutations found, a G-to-A switch and a T-to-A.
"It will be a matter of future studies to identify the proteins that interact with the hairless [protein] in skin and to elucidate their role in the development of hair," the two authors concluded.
Intravenous Immunoglobulins Reverse Deadly Skin Disease Caused By Common Medical Compounds
Flaying alive was one form of execution practiced in the Middle Ages. It involved stripping the skin from the victim's body. Nowadays, there's a (mercifully) rare disease called toxic epidermal necrolysis (TEN), which also separates large areas of skin from its victims' bodies.
TEN, also known as Lyell's syndrome, is an adverse drug reaction. It kills off keratinocytes, which are cells of the living epidermis. They produce keratin for the cuticle of the horny stratum corneum, the skin's lifeless outer layer.
TEN occurs in about one person per million. It's mostly caused by sulfonamides, the bacteria-stopping sulfa drugs, as well as by anti-convulsants and non-steroidal, anti-inflammatory medicines. About 30 percent of TEN victims die, and there is no known effective treatment.
Swiss research dermatologists at the University of Geneva Medical School set out to correct this grim state of affairs, as they report in the current issue of Science, dated Oct. 16, 1998. Their paper bears the title, "Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin [IVIG]."
CD95 is Fas, the apoptosis-triggering death receptor, which keratinocytes normally express as a prelude to epidermal detachment.
The co-authors treated 10 TEN patients with pooled human intravenous immunoglobulins. "Disease progression was rapidly reversed," their paper reports, "and outcome was favorable in all cases."
To test for the possible complicity of Fas and its ligand, FasL, the dermatologists analyzed both proteins' expression in skin samples from seven TEN patients and nine controls. They found TEN keratinocytes expressed FasL in quantity, but no excess Fas, and precipitated three- to fourfold more cell death than did controls. FasL-blocking monoclonal antibodies abrogated this effect, as did the IVIG.
"In all 10 patients, the progression of skin disease was rapidly interrupted after IVIG infusion," their paper reports, "accompanied by rapid skin healing." But they conclude that "confirmation of efficacy in the treatment of TEN will require a controlled multi-centric clinical trial."
Transgenic Mouse That Apes Huntington's Disease Hailed As 'Best-Yet' Animal Model
It's been 15 years now since molecular geneticists located the gene for Huntington's disease (HD), on the short arm of chromosome 4. That was a giant step toward detecting the neuronal defect in families. Researching therapies for HD is hampered by the fact that analysis of its neuronal defect can only be explored post mortem in the brains of deceased HD patients, which is why a faithful animal model of the disease is so critically needed.
Scientists at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health, in Bethesda, Md., are describing the experimental animal they have just created as "the best mouse model yet of Huntington's disease." Their paper in Nature Genetics for October 1998 bears the title "Behavioral abnormalities and selective neuronal loss in HD transgenic mice expressing full length IT15 cDNA."
The article's senior author, neurogeneticist Danilo Tagle, pointed out that current HD treatments "only address the symptoms and do nothing to stop the progress of neuronal cell death. If treatments can be developed based on this animal model, to prevent or delay the cell death and the debilitating symptoms of HD, that would be the best-case scenario."
The NHGRI mouse runs mindlessly in one-way circles, performs back flips, and engages in other hyperkinetic behaviors -- such as clasping its feet when suspended by the tail -- that correlate with loss of neurons in the striatum, cortex and other brain regions where HD patients also lose brain cells. Patterning the onset of HD in the mid-30s or later, the mice began to show symptoms at about 24 weeks of age. These progressed in severity for four to six weeks, followed by death within another week.
The agency expects its Huntington's stand-ins to be useful in screening for drug discovery, and for testing other therapies, including those that might assist neuron survival. *