Disease mutation tracked down, ending ‘curse’ for Colombian families

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Three years later, Joseph Arboleda-Velasquez, an HMS graduate student who led the scientific team that identified the mutations, and his collaborators have worked out an early step in the events leading from the mutated gene to the disease phenotype. The findings were published online April 27, 2005 in Human Molecular Genetics.

The new paper may help explain how the various familial mutations in a gene called Notch3 all create a similar clinical phenotype. Arboleda-Velasquez and his co-first author, Raajit Rampal, an M.D.-Ph.D. student at the State University of New York at Stony Brook, found that Notch3 mutations impair proper placement of the sugar groups necessary to control the receptor’s sensitivity to other molecules.

Specifically, the process goes askew when an enzyme called Lunatic Fringe cannot extend a chain of sugars.

Most CADASIL mutations result in a missing or extra cysteine somewhere at the end. Normally, the cysteines at the end of the receptor give the protein its accordion bends by pulling close to another cysteine. Instead, in CADASIL, an extra unpaired cysteine on one Notch3 receptor reaches out to bond with a lone cysteine on a neighboring receptor, forming an aberrant double receptor that effectively closes out Fringe.