By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.

Two rare genetic skin disorders ¿ xeroderma pigmentosum (XP) and Cockayne syndrome (CS) ¿ can blame their afflictions on a pathogen 98 million miles away, namely the sun.

That life-sustaining orb rains down ultraviolet radiation on the earth. Besides blessing green plants with photosynthesis, the sun¿s rays curse light-skinned, freckled humans with XP and CS ¿ not to mention melanoma. Riding to the rescue comes a full stable of nuclear excision repair genes, which remove damage to DNA wreaked by ultraviolet light and harmful chemicals. They control the body¿s system for editing errors in the genetic code.

But those restorative genes can themselves suffer damaging mutations, which accounts for XP and CS. Xeroderma pigmentosum strikes children at sites of the body exposed to sunburn. Skin cancer often results, with extreme sensitivity to ultraviolet light throughout adult life. XP may also inflict severe eye and neurologic abnormalities. It initially was recognized as a disease involving a more than 1,000-fold heightened risk of skin carcinogenesis from solar exposure. Once rare, XP is now common in AIDS victims. Cockayne syndrome, still unusual, features dwarfism, hypogonadism and progeria ¿ precocious wizened senile appearance ¿ as well as retinal disorders, deafness and mental retardation, along with sun sensitivity.

Now Japanese and Dutch scientists report the first evidence from an animal model that mutations in nuclear excision repair genes may be linked to abnormal brain development in XP and CS. Their paper in the Proceedings of the National Academy of Sciences (PNAS), dated Nov. 6, 2001, but released Oct. 30, bears the title: ¿Early postnatal ataxia and abnormal cerebellar development in mice lacking xeroderma pigmentosum group A and Cockayne syndrome group B DNA repair genes.¿

Mice that the authors engineered to knock out the defective nuclear repair genes, causing one or another disease, did not display the severe impairments seen in human patients. But animals deprived of both mutated genes did ¿ and died about three weeks after birth. These findings suggest that some of the early onset neurological abnormalities seen in human patients are due to defects in nuclear excision repair genes during gestational development rather than later in life. The data provide insight not only for the two rare diseases but also for the pathogenesis of human cancer and neurodegenerative diseases such as Alzheimer¿s and Parkinson¿s, as well as the aging process ¿ plus possible therapeutic approaches.

In Anti-Obesity Experiment, Knocking Out Single Gene Caused Mice To Lose Weight

Obesity is not just a hallmark of the paunchy, over-indulgent wealthy, or indolent couch potatoes. Overweight people are proliferating throughout the world, resulting in severe, global public health hazards. Treatments for this burgeoning condition are urgently needed. A consortium of biochemists, led by Canadian scientists at McGill University in Montreal, has made a move toward abating the obesity pandemic. They report identification of a protein, 4E-BP1, that can make white body fat, an energy reserve, take on the properties of brown fat ¿ a source of heat generation.

Their paper in Nature Medicine for October 2001 is titled: ¿Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1.¿ To the sizeable population of knockout mice modeling leanness and obesity resistance by diverse metabolic mechanisms, these authors have added a new lean mouse model, generated by inactivating its gene that inhibits messenger RNA translation. They found that it decreased adiposity.

A commentary accompanying this article carries a more to-the-point headline: ¿Turning WAT [white adipose tissue] into BAT [brown adipose tissue] gets rid of fat.¿ It observed, ¿In addition to revealing biological functions of the inactivated genes, these knockout mouse models may be used to identify new pharmacological targets for the treatment of obesity.¿

Quest For Crohn¿s Disease Cause ¿ Plus Possible Cure ¿ Discovers New Gene On Chromosome 5

Crohn¿s disease (CD) ¿ a.k.a. regional enteritis or inflammatory bowel disease of unknown etiology¿ ¿ spells a lifelong sentence to progressive fever, diarrhea, abdominal cramps and weight loss. Its two co-conspirators are familial inheritance and undefined environmental factors. CD surfaces most frequently in young adults under 30. There is no therapy for it, only palliative measures.

Two related articles in Medical Genetics for October 2001 update the story of CD¿s presumed cause and possible cure. One is titled: ¿High-resolution haplotype structure in the human genome¿; the other, ¿Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease.¿ They are authored by a 10-center consortium led by scientists at the MIT-affiliated Whitehead Institute Center for Genome Research in Cambridge, Mass.

CD¿s tendency to cluster in families suggests that several inherited genes play an important role in its etiology. The Whitehead investigators report discovering a gene, IBD5, located on the long arm of chromosome 5. This genomic neighborhood is home to a cluster of interleukins ¿ cytokines that bespeak immune function and inflammation. The latter correlated with CD¿s symptomology. Seeking genetic clues in the region, the team found a large block of parental gene sequences, or haplotypes, that matched up with the disease.

¿The tools and approach used to localize the IBD gene,¿ the authors point out, ¿will be broadly applicable to many complex diseases, such as asthma, diabetes, heart disease and psychiatric disorders. Understanding human variation at this level,¿ they added, ¿will have a big impact on medical genetics in the future. We now need to characterize the whole genome ¿ create haplotype maps ¿ so this type of work can be done easily for any disease.¿

Summing up their rationale, the team suggested its findings ¿set the stage for the next steps in the Human Genome Project ¿ mapping and identifying all the genes that predispose to common diseases.¿

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