Illustration of a damaged ribonucleic acid or  dna strand
[Source: Christoph Burgstedt/Getty Images]

A new genetic disorder has been discovered that is caused by a mutated version of the OTUD5 gene. Linkage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome involves a mutation that interrupts key steps in embryonic development. Studies of this defect have revealed a new molecular pathway that may be essential for human development and could also underlie other birth defects.

This work was carried out by researchers at the National Institutes of Health (NIH), and the results were reported this week in Science Advances.

LINKED joins the already more than 6,800 rare diseases known to date, which altogether affect about 25 million Americans alone. A rare disease is one that affects fewer than 200,000 people worldwide.

The project began when David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute (NHGRI) and co-first author on the paper, consulted on a male infant born with severe birth defects that included abnormalities of the brain, craniofacial skeleton, heart, and urinary tract. An examination of the baby’s siblings’ and family members’ genomes, combined with genetic bioinformatics analyses, revealed that a mutation in the OTUD5 gene was the most likely cause of the baby’s condition. Through outreach to other researchers, Beck found seven additional males ranging from 1 to 14 years of age with similar symptoms. All of them had varying mutations in the OTUD5 gene.

The OTUD5 enzyme is involved in ubiquitylation, which alters certain proteins’ functions and plays a role in governing cell fate and embryo development.

“Based on the genetic evidence, I was pretty sure OTUD5 mutations caused the disease, but I didn’t understand how this enzyme, when mutated, led to the symptoms seen in our patients,” said Beck. “For this reason we sought to work with Dr. Werner’s group, which specializes in using biochemistry to understand the functions of enzymes like OTUD5.” His  collaborator was Achim Werner, PhD, an investigator at the National Institute of Dental and Craniofacial Research (NIDCR) and lead author on the paper

The team started by examining cells from patient samples. Normally, OTUD5 edits or removes molecular tags on certain proteins to regulate their function. But in cells from patients with OTUD5 mutations, this activity was impaired.

Using a method that returns mature human cells to the stem cell-like state of embryo cells, the scientists found that OTUD5 mutations were linked to abnormalities in the development of neural crest cells.  These give rise to tissues of the craniofacial skeleton, and of neural precursors, cells that eventually give rise to the brain and spinal cord.

In further experiments, the team discovered that the OTUD5 enzyme acts on a handful of protein substrates called chromatin remodelers. This class of proteins physically alters the tightly packed strands of DNA in a cell’s nucleus to make certain genes more accessible for being turned on, or expressed.

With help from collaborators led by Pedro Rocha, PhD, an investigator at the National Institute of Child Health and Human Development (NICHD), the team found that chromatin remodelers targeted by OTUD5 help enhance expression of genes that control the cell fate of neural precursors during embryo development.

Adding all this evidence together, the researchers concluded that although OTUD5 normally keeps these chromatin remodelers from being tagged for destruction, when the gene is mutated, the enzyme’s protective function is lost and the chromatin remodelers are destroyed. That leads to abnormal development of neural precursors and neural crest cells, and, ultimately, to birth defects such as LINKED.

“Several of the chromatin remodelers OTUD5 interacts with are mutated in Coffin Siris and Cornelia de Lange syndromes, which have clinically overlapping features with LINKED syndrome,” said Werner. “This suggests that the mechanism we discovered is part of a common developmental pathway that, when mutated at various points, will lead to a spectrum of disease.”

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