Researchers from MGH and Duke University have identified genetic mutations that appear to underlie a rare but devastating syndrome combining reproductive failure with cerebellar ataxia –

Researchers from Massachusetts General Hospital (MGH) and Duke University have
identified genetic mutations that appear to underlie a rare but devastating
syndrome combining reproductive failure with cerebellar ataxia – a lack of
muscle coordination – and dementia. In a paper that will appear in the May 23
New England Journal of Medicine and is receiving early online release,
the investigators describe finding mutations in one or both of two genes
involved in a cellular process called ubiquitination in affected members of five
unrelated families.

"This study highlights, for the first time, the
importance of the ubiquitin system in a syndrome characterized by ataxia and
hypogonadotropic hypogonadism – reproductive failure due to abnormal signaling
from the brain or pituitary gland," says Stephanie Seminara, MD, of the Reproductive Endocrine Unit in the MGH Department of Medicine,
co-senior author of the report. "It also demonstrates how combining robust
genomics with detailed functional assays can unlock complex genetic

Caused by lesions in the part of the brain responsible
for coordination and balance, cerebellar ataxia can begin with difficulty
walking or speaking and progress to complete disability of those functions.
Genes associated with several syndromes characterized by ataxia have been
identified, but none had previously been associated with the rare combination of
ataxia and reproductive failure, which was first described more than 100 years
ago. Several such patients have been referred to the MGH Reproductive Endocrine
Unit, including a Palestinian family with several affected members who also
developed dementia.

Seminara notes that, while ataxia and
hypogonadotropic hypogonadism each may have several possible genetic causes, the
combination of both conditions is so rare that it is more likely to be caused by
mutations in a particular gene or related genes. In collaboration with
researchers from the Center for Human Disease Modeling at Duke – directed by
Nicholas Katsanis, PhD, co-senior author of the NEJM article – her team
conducted whole-exome sequencing of DNA from an affected member of the
Palestinian family. That screening found rare variants in both copies of 13
genes, and two of those variants were also found in samples from the patient's
two affected siblings but not in several unaffected family members.

of the mutated genes are involved in ubiquitination, a process by which cellular
proteins are marked for degredation by a protein called ubiquitin. One of them,
RNF216, codes for an enzyme that attaches ubiquitin to the protein; the other,
OTUD4, codes for a protein that removes ubiquitin. The researchers then
sequenced both of these proteins in samples from an additional nine affected
individuals from seven different families. They found that one of those
individuals had two different RNF216 mutations, four others – two in the same
family – had mutations in a single copy of that gene, but none had mutated
versions of OTUD4.

All of the individuals with RNF216 mutations had
similar medical histories, characterized by a lack of normal hormonal secretion,
progressive ataxia and dementia; and all of those with mutations in both genes
died in their 30s or 40s. Neuroimaging studies revealed similar brain
abnormalities – including atrophy of the cerebellum and cortex – in individuals
with RNF216 mutations. The four studied individuals without RNF216 mutations
had very different histories, with less severe symptoms.

To get a better
idea of the functional consequences of mutations in these two genes, the
researchers disrupted their expression in zebrafish and found that blocking
either RNF216 or OTUD4 caused disorganization of the cerebellum and reduced the
size of eyes and a portion of the midbrain. The abnormalities were even greater
when both genes were blocked but could be eliminated if production of the
relevant proteins was induced by the introduction of the corresponding human

"The presence of RNF216 mutations in several familes made its role
in causing this syndrome clear, but finding OTUD4 mutation in only one family
raised the question of whether it actually contributed to the disease or was
just an 'innocent bystander'," says Katsanis. "The zebrafish work provided
critical evidence that both genes function in a common pathway, since blocking
either of them produced similar effects. And the fact that blocking both genes
had a synergistic effect lends further evidence to the two genes' operating in
the same pathway and to the contribution of OTUD4 mutations to this syndrome."

Although exactly how these mutations lead to the symptoms seen in these
individuals is unknown, the researchers note that identifying these genes may
someday lead to therapies – potentially including drugs currently being
developed for other disorders involving ubiquitination, including Parkinson's
disease – and enable genetic screening and counseling for affected families.
They also hope to investigate whether less severe mutations in these genes may
contribute to the presence of ataxia, dementia or hypogonadism in isolation.

Seminara is an assistant professor of Medicine at Harvard Medical
School, and Katsanis is the Jean and George W. Brumley Professor of Cell Biology
and Pediatrics at Duke University Medical Center. The co-lead authors of the
NEJM report are David Margolin, MD, PhD, MGH Department of Neurology;
Maria Kousi, PhD, Duke Center for Human Disease Modeling; and Yee-Ming Chan, MD,
PhD, MGH Reproductive Endocrine Unit and Boston Children's Hospital. The study
was supported by National Institute for Child Health and Human Development
grants R01 HD043341, R01 HD042601 and U54 HD028138 and by other National
Institutes of Health grants.

Duke Medicine encompasses the Duke University Health System,
the Duke University School of Medicine, and the Duke University School of
Nursing. Its mission is to serve as a world-class academic and health care
system, working to transform medicine and health locally and globally through
innovative scientific research, rapid translation of breakthrough discoveries,
education of future clinical and scientific leaders and the highest quality of
medical practice in the community and beyond.

Clever stuff! I can't get my head around most of it, but I get the gist of it!