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Where Quality Matters Most
Chaperone genes, quality control and new views of disease
By Lone Frank

Featured Article.

We know that genetic mutations can cause disease, but in many cases the question is how they do it. For mutations that prevent the production of a gene product or interfere with its function the answer is easy. But the vast majority of the thousands of known genetic variations are so-called missense mutations—small changes that occur in parts of the gene that are not essential for function. Now, researchers are realizing that a central role may be played by what is dubbed the cell's quality control system. Understanding that role could provide new routes for treatment of genetic disease.

Protein complex of chaperones Hsp10 and Hsp60.

"We see that the effect of missense mutations can depend on how the mutated proteins interact with the cell's elaborate systems for protein handling and processing," explains biochemist Niels Gregersen, head of the Research Unit for Molecular Medicine at Denmark's Aarhus University Hospital. Among the leading investigators of quality control in mechanisms of genetic disease, he sees a new general idea forming in the field. "We hypothesize that normal variation in the quality control systems determines how cells handle proteins, and thereby how a person generally reacts to cellular stress and genetic mutations."

When it comes to protein function, three-dimensional structure is all important, and quality control systems guard this structure by forming intricate assembly lines that continuously handle and protect proteins through their life in the cell. Quality control components, which are themselves proteins, assist the folding of newly synthesized amino acid chains into functional proteins, they protect proteins from unfolding and aggregating under environmental stress, and they remove misfolded aggregates. The folding and protection is carried out by so-called 'chaperones' while the degradation is left to protein-chewing proteases.

Gregersen's theoretical model for the interaction between missense mutations and quality control systems.

Studying a rare genetic metabolic disorder ten years ago, molecular biologist Peter Bross of the Gregersen group was among the first to turn up evidence that missense mutations could cause disease through aberrant interaction with chaperones. "Such a mechanism has been proven for a handful of diseases, but evidence is gathering that a great proportion of missense mutations exert themselves through impairment of the intrinsic protein folding," explains Bross. He points to two possible outcomes. Either the cell suffers from losing the protein, which is removed because of misfolding, or the cell is destroyed by aggregates formed by misfolded protein, which quality control fails to clear.

Traditionally, monogenic diseases caused by alterations in a single gene were viewed as simple and uniform, but this is changing. "For still more of these diseases, we realize how patients carrying the exact same mutation express the associated condition in wildly different degrees. Modifying effects are clearly at work," says geneticist Lars Bolund of Aarhus University. A case in point is the enzyme disease alpha-1-antitrypsin deficiency, which causes gradual degradation of elastic lung tissue leading to emphysema. The vast majority of patients carry the so-called Z mutation, which creates a misfolded enzyme that quality control for the most part degrades and removes. However, only 10 to 15 percent of patients develop serious liver damage in childhood because aggregated enzyme collects in liver cells. "These are individuals whose quality control systems for unknown reasons cannot cope with the misfolded protein," says Bolund. Also, in well-known conditions such as cystic fibrosis and phenylketonuria, variation in quality control can determine the expression of mutations.

a possible role for quality control in the mysterious Sudden Infant Death Syndrome known as SIDS

Now, the Gregersen group wants to team with colleagues in Denmark, the United States and China for what they term a 'mega' project. The plan is to carry out the first large-scale systematic study that maps variation in quality control components and investigates the association between individual variants and disease-causing missense mutations. The disease in focus is Familial Hypercholesterolemia (FH), in which elevated levels of blood cholesterol often lead to heart disease. High cholesterol is caused by mutations in genes coding for the Low Density Lipoprotein Receptor (LDLR) and apolipoprotein B, but Gregersen points out that "these mutations alone do not explain the variation in disease outcome. Individual susceptibility plays a role and it may reside in quality control components which we know take part in maturation and turnover of LDLR and apoB."

The researchers plan to compare the entire DNA sequences of 20 known cellular chaperones and their regulatory promotor regions governing the production of chaperone protein in groups of Danish and Chinese patients and healthy controls. "The variants we come up with will then be tested in functional assays to clarify their biological effect," explains Bross. Apart from answering questions specifically about FH, the team hopes their project will spur further inquiries into the general role of quality control. When a map of variation is available, scientists in different fields can readily investigate its implication in any given genetic disease, "or normal traits for that matter," adds Gregersen.

Another joint Aarhus-Beijing project centers on a possible role for quality control in the mysterious Sudden Infant Death Syndrome known as SIDS. According to one recent hypothesis, a sudden rise in the baby's temperature is the killer. "Functional defects in quality control could make the infant unable to cope with the stress of fever," says molecular biologist Jan Jakob Hansen. Huanming Yang of the Beijing Human Genome Center and Hansen are looking for variation in the chaperones Hsp10 and Hsp60, which play crucial parts in the normal response to high temperatures. DNA from biopsies of all Danish SIDS victims since 1989 is being sequenced and compared to controls. Already, the functional effect of one variation found in a dead infant in a pilot study is being investigated.

The investigation of the modifying effect of cellular quality control is a young field of research, but, according to Bolund, it is meeting with rising interest among geneticists and biochemists. Although the clinical implications are not yet in sight, researchers envision that the knowledge they forge will open new avenues for treating diseases caused by missense mutations. Initial findings in animal experiments suggest that symptoms of alpha-1-antitrypsin deficiency can be alleviated by treatment with chemical chaperones. "A deeper understanding of quality control systems will allow us to manipulate them rationally," says Gregersen, and, as a geneticist, Bolund emphasizes that the interest in quality control is part of a growing movement. "We are realizing that genetic function is enormously complex, and that this is one important layer of complexity."

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Gregersen, N., Bross, P., Jørgensen, M.M., Cordydon, T.J. & Andresen, B.S. Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders. J Inherit Metab Dis 23, 441-447 (2000).
Bross, P., Corydon, T.J., Andresen, B.S., Jørgensen, M.M., Bolund, L. & Gregersen, N. Protein misfolding and degradation in genetic diseases. Hum Mutat 14, 186-198 (1999).
Perlmutter, D.H. Alpha-1-antitrypsin deficiency. Semin Liver Dis 18, 217-225 (1998).

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