Next to cystic fibrosis, the commonest lethal, recessive, autosomalgenetic disease among Caucasians is spinal muscular atrophy(SMA). Its severest form, infantile progressive SMA (type I), killsbabies half way through their first year of life, on average. Lifeceases because their wasted muscles render breathing impossible.

In this neuromuscular disease, death of spinal cord motor neuronsbrings on atrophy of skeletal muscles.

There is no treatment for SMA, no cure, and as yet very little insightinto the genetic cause of this disease, which occurs only when bothparents contribute (homozygously) a lethally mutated gene to theiroffspring's genome. Clinical diagnosis is by linkage analysis ofrestriction fragment length polymorphisms.

Besides its early-death version, SMA also strikes in two gentlerchildhood-onset forms: Intermediate type II spares its small victimsfor up to three years of tortured muscle-wasting existence; juveniletype III, for one to 15 years of life.

Molecular geneticists from a score of independently workingresearch centers in eight countries of Europe, North America andJapan reported last October at the 1994 meeting of the AmericanSociety of Human Genetics that they are closing in on the hyper-elusive mutant gene, which they have now tracked down to the longarm of human chromosome 5.

And this month, Nature Genetics, January 1995, and Cell, Jan. 13,report progress by U.S. and French centers in bringing the SMAgene to book.

In the biological chemistry laboratory of John Wasmuth at theUniversity of California, Irvine, molecular geneticist TerriThompson is first author of the Nature Genetics paper, titled, "Anovel cDNA detects homozygous microdeletions in greater than 50percent of type I spinal muscular atrophy patients."

They and their co-authors reported that a genomic fragment detectedby one complementary DNA on chromosome 5 is homozygouslydeleted in 17 of 29 type I SMA patients (58 percent). Of 235 normalindividuals they examined, only two showed the deletion, and bothare SMA carriers. They call their defective gene XS2G3.

The Muscular Dystrophy Association, based in Tucson, Ariz., saysthat SMA occurs only once in 10,000 births, and that currently twicethat number of Americans have some form of the disease.

The association funds much of the ongoing SMA research in theU.S. with $20 million allocated to studying it thus far. Theassociation's director of science technology, Donald Wood,welcomed the Irvine report as "a long-anticipated finding that shouldquickly improve accuracy in diagnosis of the forms of SMA."

He added, "Most important, it will accelerate our continued searchfor a form of treatment. Because of the unusual complexity of thechromosomal region involved, it's important that other studies verifythe findings."

That "unusually complex" region of chromosome 5, first authorThompson told BioWorld Today, is known among researchers as"the junkyard." She explained: "What people have been finding isthat repetitive elements on both arms of chromosome 5 contain a lotof pseudogenes that are transcribed."

Pseudogenes by definition are seldom if ever transcribed. Thompsonobserved that "Nobody has any clue as to their possible function. Wejust keep pulling out these things that map to other areas of thegenome. So it's hard to tell if they're a functional copy or not. It's sodifferent from the rest of the human genome We don't know what'sreal and what's not real."

The gene that she and her co-authors discovered detects deletions inthe genomes of type I patients. "This gene," she observed, "has nohomology to anything in the data base. So I don't have any idea as toits function. It has to be a mutant of a normal copy. People withoutthe missing portion of the gene are fine."

But she has no idea what the normal gene looks like.

In back-to-back papers, Arnold Munnich of the Hospital for SickChildren in Paris and Alix MacKenzie of the University of Ottawareport in Cell isolation of other SMA gene deletions on chromosome5. Irvine's Thompson observed, "Our three laboratories are stilltrying to decipher everything right now. The lab that seems to havethe best numbers and the highest percentage of mutations isMunnich's French group." n

-- David N. Leff Science Editor

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