Editor's note: Science Scan is a roundup of recently publishedbiotechnology-related research.

Some inherited diseases, such as Alzheimer's, are named for thephysicians who discovered and described them. Other geneticdisorders, e.g., Lou Gehrig's disease (amyotrophic lateral sclerosis),memorialize their victims.

If such a sufferer's name is ever attached to the rare inherited bonedisease called pycnodysostosis, it might well bear the eponym,"Toulouse-Lautrec disease." Henri-Marie-Raymonde de Toulouse-Lautrec-Monfa (1864-1901) was the off-beat Parisian artist whoseposters immortalized life at the Moulin Rouge in Montmartre. Hislifelong disability _ stunted stature, flattened facial features,multiple skeletal deformities _ has recently (but controversially)been retrospectively diagnosed as pycnodysostosis (Pycno for short).

Now, by genomic analysis of several extended Pycno familiesworldwide, molecular geneticists at Mount Sinai School of Medicinein New York have found three mutations in a gene on the long arm ofhuman chromosome 1. They apparently account for Pycno, anautosomal recessive trait. The title of their paper in Science, datedAug. 30, 1996, sums up their findings: "Pycnodysostosis, a lysosomaldisease caused by cathepsin K deficiency."

Cathepsin K is one of the numerous enzymes in a cell's lysosomesthat break up and remove proteins no longer needed in the body.Searching the genomes of Pycno patients, the researchers detectednonsense, missense and stop-codon mutations in the sequenceencoding cathepsin K.

When they expressed a full-length complementary DNA containingthe stop-codon mutation, it produced messenger RNA, but nodetectable cathepsin K. This protease normally occurs in osteoclasts.These cells specialize in normal bone-matrix resorption, that is,flushing away surplus osseous tissue.

The team's authors conclude that Pycno, a pure skeletal dysplasia, isa lysosomal disorder, which provides "a possible rationale for thetreatment of disorders such as osteoporosis and certain forms ofarthritis."

Mice Missing Nerve Factors For Breathing Hint At Therapy ForSudden Infant Death Syndrome

Ondine's Curse is an eponym of a different stripe.

For one thing, Ondine was neither physician nor patient. Paracelsus,the 16th-century Swiss alchemist and physician, who coined theconcepts of disease and drug therapy, defined "Undine" as a femalewater spirit who could earn a soul by bearing a mortal's child.

Sleep therapists define Ondine's Curse as congenital chronichypoventilation syndrome, in which involuntary (but not voluntary)control of respiration is depressed. In the orchestra of vascular,visceral, muscular and brain impulses that govern normal, automaticbreathing, the baton is carbon dioxide.

The concentration of this gas, CO2, in arterial blood bathing braincells, nudges certain respiratory neurons to step up or step downinhalation and exhalation, in response to a body's spot-need for moreor less oxygen.

Within that mission-control center in charge of respiration, a networkof neurotrophic factors operates the system. Two of those moleculesin particular, Brain-Derived Neurotrophic Factor (BDNF) andNeurotrophin-4/5 (NT4), apparently focus on breathing regulation.

To dissect the separate or combined effects of BDNF and NT4,neuroscientists investigated transgenic mice lacking the factors'genes. The title of their report in the September 1996 Journal ofNeuroscience tells the result: "Mice lacking brain-derivedneurotrophic factor [BDNF] exhibit visceral sensory neuron lossesdistinct from mice lacking NT4, and display a severe developmentaldeficit in control of breathing."

A research group at Regeneron Pharmaceuticals Inc. in Tarrytown,N.Y., constructed the BDNF-minus mice, in collaboration withAmgen Inc., of Thousand Oaks, Calif., and SumitomoPharmaceutical Co. Ltd., of Osaka, Japan.

Neuroscientist David Katz, at Case Western Reserve University inCleveland, is the article's senior author. A co-author, GeorgeYancopoulos, Regeneron's vice-president, discovery, observed: "Thework of Dr. Katz and his colleagues may lead to new treatmentpossibilities for patients with breathing disorders."

Katz concluded: "Particularly intriguing are possible relationshipsbetween the mechanisms underlying normal breathing in the mutantmice and disorders such as sudden infant death syndrome (SIDS),sleep apnea [breathing cessation] and Ondine's Curse in humanpatients."

Another Human Victim Of Mad Cow DIsease? Tumor NecrosisFactor's Sinister Role

A fourth British dairy farmer has come down with Creutzfeldt-Jakobdisease (CJD), according to a letter in this week's Lancet, dated Sept.7. All four had had contact with cattle affected by mad cow disease_ bovine spongiform encephalopay (BSE). (See BioWorld Today,April 8, 1996, p. 1.)

Its authors, at the National Creutzfeldt-Jakob Disease SurveillanceUnit in Edinburgh, Scotland, observe: "The apparent excess of recentcases of CJD in the U.K. occurring in people exposed to cattleaffected with BSE has increased speculation that CJD may resultfrom its transmission to human beings."

At the molecular level, neurovirologist D. Carleton Gajusek, at theU.S. National Institute of Neurological DIsorders and Stroke, (whowon a Nobel prize for elucidating kuru, the first spongiformencephalopathy disease in 1969), reports findings in the currentProceedings of the National Academy of Sciences from which heconcluded: "Overexpression of tumor necrosis factor-a inneurodegenerative diseases as diverse as CJD, AIDS . . . and multiplesclerosis suggests that pro-inflammatory lymphocytes may act as end-stage mediators of axon and myelin damage, irrespective of itscause." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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