Cholesterol and NPC1, circa 1997

NPC1's amino acid sequence homology to PATCHED, human HMG-CoA reductase and SCAP. Credit: Reprinted with permission from AAAS / Carstea et al., Science 277:228, 1997.

By | November 1, 2008

<figcaption>NPC1's amino acid sequence homology to PATCHED, human HMG-CoA
                    reductase and SCAP. Credit: Reprinted with permission from AAAS / Carstea et al., Science 277:228, 1997.</figcaption>
NPC1's amino acid sequence homology to PATCHED, human HMG-CoA reductase and SCAP. Credit: Reprinted with permission from AAAS / Carstea et al., Science 277:228, 1997.

In the 1990s, the Ara Parseghian Foundation donated money to the National Institutes of Health to sequence the gene associated with a rare disease affecting the three grandchildren of Parseghian, the famed Notre Dame football coach. At the time, only a handful of labs in the world were working on Niemann Pick C, a neurodegenerative disorder known to strike one in 150,000 people.

Researchers knew the NPC1 gene was behind most cases of NPC, and the disease was characterized by an accumulation of cholesterol in the lysosomes. But they were unsure of the location of the gene and how the protein functioned. Through integrated human-mouse positional cloning, researchers were able to narrow in on the NPC1 gene.

After plugging the DNA sequence of the NPC1 gene into the National Center for Biotechnology Information (NCBI) database, Jill Morris, a postdoc at NIH, remembers the excitement found within the 30-page print-out - the protein shared homology with 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and sterol-regulatory element binding protein (SRP) cleavage-activating protein (SCAP), two proteins known to be involved in moving cholesterol in the cell, and PATCHED, a protein well-studied for its role in Hedgehog signaling in Drosophila (Science, 277:228-31, 1997).

Researchers immediately recognized the significance of the connection between NPC1 and other more well-studied proteins, says Bill Pavan, a molecular biologist who was part of the team and now works with animal models of skin disease at the NIH.

"By having links between this rare, understudied disease and these other areas of active research, I was excited to see we could attract additional researchers … to help understand how mutation of the protein is involved in Niemann Pick C disease," Pavan says. Today, the Ara Parseghian Foundation funds 26 research projects into NPC and other cholesterol-related diseases, including cardiovascular disease and Alzheimer's disease (see "Twin disorders").

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