DOE Clone Resources Spur Disease-Gene Discoveries

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By:Aaron Hall

Migraine

Two research groups report results suggesting a common genetic cause for migraine and epilepsy and the availability of an animal model that may be useful for further studies. Both groups used the chromosome 19 physical map and selected clones supplied by the Human Genome Center at Lawrence Livermore National Laboratory (LLNL).

Researchers led by Lisa Stubbs at Oak Ridge National Laboratory (ORNL) reported the isolation, mapping, and expression analysis of the chromosome 8 CACNL1A4 gene found in the mutant "tottering" mice studied extensively as models for human epilepsy and cerebeller ataxia. The mouse CACNL1A4 region is homologous to a human chromosome 19 region previously implicated in episodic ataxia type 2 and familial hemiplegic migraine (an inherited form of migraine). Now the ORNL studies indicate that mutations in the human CACNL1A4 gene are indeed the causative factor in both disorders. Tottering mutants may thus represent mouse models of both diseases, according to the authors of the Mammalian Genome article in press. In the November 15 issue of Cell, Fletcher et al. published evidence that a calcium channel gene is responsible for tottering and leaner alleles.

Roel A. Ophoff and colleagues at Leiden University in The Netherlands, in collaboration with LLNL genome center scientists, reported cloning the human gene CACNL1A4. This gene contains two different mutations that they associated with familial hemiplegic migraine and episodic ataxia type 2. The research findings were - included in the November 1, 1996, issue of the journal Cell. The authors noted that although these kinds of migraine are rare, variations in the same gene may predispose people to the more common migraine, which affects an estimated 24% of women and 12% of men.

The implicated gene affects the transport of calcium into specific classes of brain cells. This calcium movement regulates the release of neurotransmitters - critical elements in the communication network among cells of the nervous system. Further explorations into the structure and function of the gene will improve diagnosis and may aid in development of new treatments for migraine.

In addition to the role of genes suggested by family, twin, and population studies, such other factors as emotional stress and certain foods and additives have been associated with migraine attacks.

Chromosome Resources a Boon to Gene Hunters

The physical map spanning the candidate region was constructed from the chromosome 19 flow-sorted library generated by LLNL as an early part of the National Laboratory Gene Library Project. In this project, researchers at LLNL and Los Alamos National Laboratory (LANL) used flow sorters equipped with lasers to separate human DNA into individual collections (libraries) of each of the 24 different human chromosomes.

LLNL chromosome 19 libraries also have been important in studies leading to the identification of other genetic mutations, including those associated with a syndrome characterized by recurrent strokes and progressive dementia .

"These clones have proven invaluable to biologists and medical scientists who are conducting more focused and specialized studies," observed Harvey Mohrenweiser, senior biomedical scientist at the LLNL Human Genome Center. "It's exciting to be participating in such collaborations, especially when these discoveries may have a significant, positive impact on a sizable portion of the population."

Fanconi Anemia

Chromosome 16 resources generated by scientists at LLNL and LANL were instrumental to the recent isolation of a mutated gene associated with Fanconi anemia (FA). FA is a rare autosomal recessive disease characterized by skeletal abnormalities, bone marrow failure, and a predisposition to cancer. In the November 1996 issue of Nature Genetics (14, 240-42, 320-28), researchers reported finding a gene associated with FA, subtype A, one of five subtypes described for the usually fatal disorder.

In addition to the discovery's considerable impact on the diagnosis and eventual treatment of FA patients, researchers hope that a better understanding of the FA gene pathway will shed light on developmental processes. The multiple clinical abnormalities associated with the disorder suggest that FA proteins play an important part in the development of many organ systems, and researchers believe faulty cellular defense or DNA repair mechanisms are to blame. The protein predicted by the FAA gene has no homology to other known proteins, which suggests a novel pathway not related to known mechanisms of defense and repair.

An international consortium composed of research groups from Australia, Italy, The Netherlands, South Africa, United Kingdom, and United States was responsible for the Nature Genetics report.

Stroke and Dementia

In the October 24, 1996, issue of Nature [383 (673), 707-10], researchers reported finding mutations in Notch3, a chromosome 19 gene associated with CADASIL, a hereditary adult-onset condition causing recurrent strokes and progressive dementia. The chromosome 19 map from LLNL was an important resource for the initial studies.

Symptoms of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) appear at about age 45, with patients usually dying by 65. The number of affected individuals is unknown, and the condition is thought to be largely undiagnosed. The Nature authors noted that stroke is the third leading overall cause of death, and vascular dementia is the second leading cause of dementia after Alzheimer's disease.

Notch3, the gene implicated in CADASIL, belongs to a gene family whose functions are essential to embryonic development; Notch genes are found in species as diverse as insects, roundworms, and mammals. Involvement of Notch3 in CADASIL suggests that disruption of the Notch signaling pathway may be a key factor in adult-onset conditions causing dementia, such as Alzheimer's disease. Researchers hope that studies on the function of the protein encoded by the Notch3 gene will yield further clues into the pathogenesis of adult-onset dementia and stroke.

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