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.

Adapted from the original courtesty of Christine Seidman

Both the mild Björnstad syndrome and the lethal Complex III deficiency are caused by mutations in the BCS1L (pink), which chaperones (solid arrows) an essential iron-sulfur protein (red) into the mitochondrial respirasome (gray). In Björnstad syndrome, the BCS1L complex fails to form, while in Complex III deficiency, it fails to hydrolyze ATP. Both mutations compromise respirasome formation (dashed arrow.)

“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.

—Tom Fagan

Key Molecule in Brain Development Tied to Tumor Growth

In recent years, cancer biologists have shown that the growth of solid tumors may be driven by a minor subpopulation of cells that behave as stem cells. The identification of these cells in tumors has fueled the search for underlying growth regulatory mechanisms in normal stem cells whose misregulation might cause cancerous transformation. One such study conducted by researchers from Dana–Farber Cancer Institute has succeeded in identifying a transcription factor, previously known as a vital component of normal brain development, to be critical for brain tumor formation. The work was conducted in the labs of Charles Stiles, HMS professor of microbiology and molecular genetics, and David Rowitch, formerly an HMS associate professor of pediatrics. Postdocs Keith Ligon, Emmanuelle Huillard, and Shwetal Mehta contributed equally to this work, which appears in the Feb. 15 Neuron.

The researchers studied Olig2, a transcription factor that is specifically expressed in multipotent neural progenitor cells (stem cells) of the developing central nervous system. During normal development, a key function of Olig2 is to prevent differentiation and maintain neural stem cells in a replication-competent state until a sufficient number of cells are available to undergo differentiation and assemble an intact brain.

Human glioblastoma samples show the presence of tumor progenitor cells, which bear similarities to normal neural stem cells and are likely derived from them. Ninety-eight percent of these cells, named CD133, express Olig2. This observation motivated the researchers to interrogate the role of Olig2 in tumor development.

The authors showed that Olig2 function is crucial for tumor development in a mouse model of malignant glioma that emulates the genetic mutations seen commonly in human malignant gliomas. The absence of Olig2 in the context of an otherwise tumor-promoting genetic background prevented the growth of tumors in the brains of immunocompromised mice; the ability to form tumors was rescued by reintroduction of the Olig2 gene. On a mechanistic level, the research team identified a cell cycle inhibitor molecule, p21, whose expression is repressed by Olig2, which may be a key event allowing uncontrolled proliferation of tumor cells.

This research highlights the role of developmental regulators in facilitation, if not initiation, of cancer progression. Whereas loss of tumor suppressors such as p53 is a familiar feature in cancers of most tissue types, knowledge about tissue-specific factors that are critical for tumorigenesis is still lacking. The current study fills this gap with the identification of Olig2 as a lineage-specific transcription repressor whose aberrant expression in neural stem cells can be a precursor to malignancy.

—Amita Joshi

Knee Replacement Data Show Vulnerable Populations More Likely to Select Low-volume Hospitals

Patients who live in socially or economically vulnerable neighborhoods are more likely to use low-volume hospitals for total knee replacement surgery, and even bypass a closer, high-volume hospital to do so. That is the conclusion of a nationwide study led by Jeffrey N. Katz, an HMS associate professor of medicine and of orthopedic surgery at Brigham and Women’s Hospital and an HSPH associate professor in the Departments of Environmental Health and of Health Policy and Management, and Elena Losina, HMS visiting associate professor of orthopedic surgery at BWH. Their paper appears in the Jan. 22 Archives of Internal Medicine.

“The findings speak to the potential disparities in health care because not only are patients from vulnerable populations less likely to use these types of procedure, but those who do utilize them end up in centers with potentially worse outcomes,” said Losina, the lead author on the paper.

It is well accepted that for surgeries such as total knee replacement, higher volume hospitals have better outcomes, but it is not clear whether that message is getting across to the general population, particularly minorities and those with low incomes or low levels of education. The study suggests that it is not.

Losina and colleagues used nationwide Medicare claims data to identify more than 100,000 people who had elective total knee replacement surgery and then correlated their neighborhood status with hospital use. The researchers found that those who were from neighborhoods with one, two, or three of the four defined vulnerability factors (a high proportion of minority, foreign-born, low-income, or low-education residents) were 1.3, 1.5, and 2.0 times more likely to use a low-volume hospital. If patients came from urban neighborhoods where more than 25 percent of the population is below the poverty line and more than 50 percent are minorities, they were twice as likely to bypass a high-volume hospital.

Given the aging population and the increasing incidence of arthritis, the data are troubling. “There is concern that in more vulnerable neighborhoods, poor outcomes relayed by word-of-mouth could deter patients from total knee replacements, which are more than 90 percent successful, dramatically increasing mobility and improving quality of life in the elderly,” said Losina.

—Tom Fagan

Study Upends Convention, Finds Methylation Greater on Activated than Inactivated X

By using a modified microarray technique, HMS geneticists have identified a surprising feature of how one of the two copies of the X chromosome in females is silenced. The researchers looked at patterns of DNA methylation, a mechanism associated with silencing, and found that it is more concentrated on the activated X chromosome. The discovery, reported in the Feb. 23 Science, overturns the dogma that methylation occurs mainly on the inactivated X.

Proper dosage of gene products requires turning off one of the two Xs that females inherit. Choosing to silence the maternal or the paternal X chromosome is a random event, occurring on a cell-by-cell basis. Once that choice is made early in development, it is maintained through subsequent cell divisions.

DNA methylation has become recognized as central for maintaining the silenced state of genes. In humans, methyl groups bind to CpG DNA sequences, where a cytosine nucleotide links with a guanine nucleotide.

Research fellow Asaf Hellman and HMS professor of medicine Andrew Chess, both at Massachusetts General Hospital’s Center for Human Genetic Research, compared methylation on activated and inactivated X chromosomes. They incubated human immune cells with an enzyme that cuts DNA wherever it is unmethylated. Then they loaded the sample onto a gene chip that can probe thousands of sites on the X chromosome. The NIH-funded study showed that methylation was two times greater on the activated X than on the inactivated X and that the X active–specific methylations concentrate at the transcribed regions of genes.

The team’s approach of looking at many sites at once contrasts with previous work, which has been limited to studying a select few CpG sites and has led to the belief that methylation is more abundant on inactivated sites. “You used to have to pick out a candidate; now you can look across the entire genome,” Chess said.

Understanding patterns of DNA methylation may be a new key in deciphering and treating inheritable diseases, including cardiovascular disease, diabetes, and schizophrenia.

—Molly McElroy

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