First identification of the genetic basis of disease in a patient with a complex I assembly defect

Mitochondrial complex I deficiency is one of the most common defects in patients with mitochondrial disease. The deficiency results from a failure to assemble the enzyme properly, but the nature of the molecular chaperones that are necessary for this process in mammals have remained obscure.

In a new study appearing on October 3 in The Journal of Clinical Investigation, Eric Shoubridge and colleagues McGill University identify candidate proteins involved in complex I assembly, and show that one of the candidates, B17.2L, is an assembly factor. The authors identify a null mutation in a patient with a progressive encephalopathy, and show that the defect can be functionally complemented by expression of the wild-type cDNA in patient cells. They also show that an antibody against the B17.2L protein recognizes a subassembly of complex I in several additional patients with complex I assembly defects, but not the whole enzyme complex itself, consistent with a role as a molecular chaperone.

This is the first molecular chaperone to be characterized for mammalian complex I, and is the first identification of the genetic basis of disease in a patient with a complex I assembly defect.

In a related commentary, Robert Nussbaum writes, "The research described here combines clever model organism genomics and bioinformatics to identify the first mammalian protein required for the normal assembly of complex I."

http://www.jci.org/

A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy