Familial hypercholesterolemia, a genetic disease characterized by high
levels of cholesterol and early mortality, is caused by defects in the receptor
for the low-density lipoprotein (LDL) Protein folding defects have also been implicated in other human
diseases, including cystic fibrosis, a-1-antitrypsin deficiency, retinitis
pigmentosa, and Marfan1s syndrome. 3Our studies provide yet another example of
how basic science research, such as studies of protein folding, ultimately help
us understand human disease,2 says Dr. Kim.
Normally, cholesterol is removed from the bloodstream and taken into
cells by the LDL receptor on the cell surface. Scientists have known that a
defective LDL receptor results in high levels of blood cholesterol. In most
cases of familial hypercholesterolemia, this happens because the gene for the
LDL receptor is slightly mutated.
In the Whitehead-HHMI study, researchers studied a critical fragment of
the LDL receptor that frequently contains single amino acid mutations in
patients with
familial hypercholesterolemia. 3We found that the normal copy of this crucial
fragment folds into its proper shape, but introducing even single mutations in
the fragment interferes with the fragment1s ability to fold into this shape,2
says Dr. Blacklow. Combining nuclear magnetic resonance (NMR) spectroscopy and
other biochemical methods, researchers also found that the normal copy of this
fragment was unable to fold properly in the absence of calcium, and adding
calcium restored its folding ability. Based on these data and other biochemical
information, researchers speculate that the mutations in the LDL receptor affect
the receptor1s ability to bind calcium and therefore its ability to fold into
its proper shape.
This work was funded in part by the National Heart, Lung and Blood
Institute.
Background
Familial hypercholesterolemia (FH) is an autosomal dominant trait,
meaning that a child born to an affected parent has a 50 percent chance of
inheriting the gene. About 1 in 500 people are heterozygous for FH
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