Mutation Pinpointed Behind Hearing and Hair Loss of Björnstad Syndrome

HMS researchers have identified the mutation that causes Björnstad syndrome, a rare, recessive disorder that causes hearing and hair loss. The latter is due to pili torti, an irregular 180-degree twisting of hair strands that makes them extremely brittle. Surprisingly, the mutation lies in the gene for the mitochondrial chaperone BCS1L, which plays a crucial role in the assembly of the mitochondrial electron transport chain. BCS1L mutations are also responsible for complex III deficiency and GRACILE syndrome, lethal diseases that cause profound systemic organ failure.

“BCS1L was the last place we thought we’d find the Björnstad syndrome mutation,” said Christine Seidman, a Howard Hughes investigator, the Thomas W. Smith professor of medicine at Brigham and Women’s Hospital, and professor of genetics at HMS. She is joint senior investigator on the study together with Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation professor of genetics at HMS (who is also her husband), and Roland Eavey, HMS professor of otology and laryngology at Massachusetts Eye and Ear Infirmary. The findings appear in the Feb. 22 New England Journal of Medicine.

“The discovery is thanks to the tenacity of an extraordinarily talented medical student, Travis Hinson,” said Christine Seidman. Earlier gene mapping by the Seidman lab had identified 47 genes, including BCS1L, that could harbor the Björnstad syndrome mutation. But given the lethality of complex III deficiency and GRACILE syndrome, the gene was not considered a likely candidate. Hinson, lead author on the paper, sequenced 44 of the 47 genes before finally pinpointing the mutation, a single nucleotide variation that results in a histidine instead of an arginine at position 183 of the 419–amino acid chaperone.

The mutation prevents the normal assembly of BCS1L monomers into a hexameric unit that guides the Rieske iron–sulfur protein into complex III of the mitochondrial respiratory chain (see diagram). In the absence of the iron–sulfur protein, electron transport through complex III is inefficient and instead of being funneled through the chain to cytochrome oxidase, where they are combined with oxygen to form water, electrons leak out of the chain to form toxic reactive oxygen species (ROS). The mutations that cause complex III deficiency and GRACILE syndrome lead to a similar outcome because they prevent the BCS1L complex from hydrolyzing ATP, which helps drive complex III assembly.

So why are GRACILE syndrome and complex III deficiency so lethal? That appears to be due to complete absence of functional BCS1L, which may trigger stimuli that increase the numbers of mitochondria, leading to an even greater increase in ROS. As for the apparent tissue specificity of Björnstad syndrome, “that is because hair and hearing are exquisitely sensitive to mitochondrial defects,” said Seidman. She suggested that might also explain age-related hair and hearing loss.