'Candidate' Defect Is Found In Huntington's Disease Gene

The Harvard Medical School researcher who nine years ago discovered the general location of the DNA sequence responsible for Huntington's disease reports today that he and a team of researchers may be one step closer to completing the search for a precise identification of that gene.

James F. Gusella, professor of genetics at the Medical School, reports in an article in today's issue of Nature Genetics, a British scientific journal, that he and co-workers at the Massachusetts General Hospital have discovered a gene coding for a defect which may be responsible for the disease.

Symptoms of the degenerative brain disorder, which usually begin to appear in middle age, include a progressive loss of control over all the muscles of the body. Patients often exhibit a decline in cognitive function and sometimes dementia, and the disorder is fatal.

Since 1983, when Gusella first determined that the gene for Huntington's was located on the tip of the short arm of chromosome four, scientists have been engaged in a quest to define the exact nature of the biochemical abnormality, thought to be a defective protein or enzyme, which is responsible for its symptoms.

Although the Huntington's gene was one of thefirst human genes to be localized to a specificchromosome, a number of possible abnormalitiesstill exist.

In a paper published last April, Gusella andhis colleagues demonstrated that 30 to 40 percentof DNA collected from Huntington's diseasepatients and their families share a short segmentof approximately 500,000 base pairs on thechromosome.

Today's article presents findings that the DNAsequence coding for alpha-adducin, a proteinpresent in high concentrations in the brain andtherefore possibly linked to the disease, is amongthe sequences present in that short segment.

One hypothesis advanced by some researchers isthat Huntington's disease is caused by a defect insome protein, present in cells throughout thebody, to which a certain class of neurons, whichdisappear during the course of a patient's life,are more sensitive.

Adducin, made of subunits alpha and beta, bindsto another molecule, calmodulin, which is thoughtto be important in the synthesis of the membranesof cells throughout the body. A high level ofadducin in the brain raises the possibility thatthe protein is somehow involved in neural functionor even those neurons associated with Huntington'sdisease.

The results are part of a full investigation ofa larger segment of the chromosome, approximatelyfour times as long, to which the gene has beenlocalized. Assistant Professor of Neurology MarcyE. MacDonald, a co-author of the article, saidyesterday that a great deal of work remains to bedone to isolate other molecular candidates forHuntington's-related defects.

"We don't want to give people the idea that adefect in this particular gene is responsible forHuntington's disease," MacDonald said. "We want toput into the public domain all the candidates aspotential defects and encourage other labs to lookat them."

In carrying out their research, Gusella's grouputilized a relatively new technique invented byanother co-author, University of Wales geneticistAlan Buckler, which allows better identificationof those genes which actually translate into agiven protein, in this case alpha-adducin.

Sequences of DNA contain large segments, calledintrons, which are not actually translated intothe protein formed. This often makes finding thosegenes responsible for a given protein--the exonswhich lie between the introns--extremely difficultfor researchers, who must sift through as much as98 or 99 percent "junk" DNA.

MacDonald said that Buckley's technique, knownas exon amplification, clones introns and presentsthe scientist with only those sequences of DNAactually responsible for translation of theprotein. Using this data, workers in Gusella'sgroup were able to screen a database of DNAsequences and identify introns for adducin asthose they identified

Although the Huntington's gene was one of thefirst human genes to be localized to a specificchromosome, a number of possible abnormalitiesstill exist.

In a paper published last April, Gusella andhis colleagues demonstrated that 30 to 40 percentof DNA collected from Huntington's diseasepatients and their families share a short segmentof approximately 500,000 base pairs on thechromosome.

Today's article presents findings that the DNAsequence coding for alpha-adducin, a proteinpresent in high concentrations in the brain andtherefore possibly linked to the disease, is amongthe sequences present in that short segment.

One hypothesis advanced by some researchers isthat Huntington's disease is caused by a defect insome protein, present in cells throughout thebody, to which a certain class of neurons, whichdisappear during the course of a patient's life,are more sensitive.

Adducin, made of subunits alpha and beta, bindsto another molecule, calmodulin, which is thoughtto be important in the synthesis of the membranesof cells throughout the body. A high level ofadducin in the brain raises the possibility thatthe protein is somehow involved in neural functionor even those neurons associated with Huntington'sdisease.

The results are part of a full investigation ofa larger segment of the chromosome, approximatelyfour times as long, to which the gene has beenlocalized. Assistant Professor of Neurology MarcyE. MacDonald, a co-author of the article, saidyesterday that a great deal of work remains to bedone to isolate other molecular candidates forHuntington's-related defects.

"We don't want to give people the idea that adefect in this particular gene is responsible forHuntington's disease," MacDonald said. "We want toput into the public domain all the candidates aspotential defects and encourage other labs to lookat them."

In carrying out their research, Gusella's grouputilized a relatively new technique invented byanother co-author, University of Wales geneticistAlan Buckler, which allows better identificationof those genes which actually translate into agiven protein, in this case alpha-adducin.

Sequences of DNA contain large segments, calledintrons, which are not actually translated intothe protein formed. This often makes finding thosegenes responsible for a given protein--the exonswhich lie between the introns--extremely difficultfor researchers, who must sift through as much as98 or 99 percent "junk" DNA.

MacDonald said that Buckley's technique, knownas exon amplification, clones introns and presentsthe scientist with only those sequences of DNAactually responsible for translation of theprotein. Using this data, workers in Gusella'sgroup were able to screen a database of DNAsequences and identify introns for adducin asthose they identified