Xing lab works with patient family to cure rare genetic mutation

Dr. Xing and patient Jordan sitting in front of art piece made by patient families

Dr. Yongna Xing and Jordan Lang, March 2019 in front of angel’s wings made by patient families.

Jordan’s parents spent years visiting doctors to find out why their baby girl wasn’t meeting developmental milestones. After getting a diagnosis in 2016 by whole-exome sequencing, they began connecting researchers and patient families to collaborate and learn more about their daughter’s genetic mutation, which is now known as Jordan’s Syndrome.

Dr. Yongna Xing is a part of that research team.

The patient families are amazed that all of their kids’ symptoms are caused by a single nucleotide alteration in the PPP2R5D gene, said Xing.

“The mutation leads to a wide range of neurological symptoms, including intellectual disabilities, loss of or reduced verbal skills, autism, mild seizures, and hypotonia, which means that their muscles do not function properly.” she said.

Very few patients get diagnosed because so little is known about the syndrome, and molecular diagnosis by whole-exome sequencing is not widely used. Jordan wasn’t diagnosed until she was 9 years old after a whole exome sequencing test. The test allowed doctors to search her whole genome for mutations leading them to the diagnosis that left them with very few answers.

Jordan’s parents started a foundation to do as much as they could to increase resources for their daughter and help other affected families.

The Jordan’s Guardian Angels Foundation connects families affected by Jordan’s Syndrome, raises awareness and research support, and compiles PPP2R5D research from around the world.

Today, the PPP2R5D intellectual disability (ID) mutations have been found in more than 100 children from 21 months to 25 years old in 19 countries across the globe, with more children being diagnosed each month. It is estimated that 250,000 cases are undiagnosed.

“The patient’s family is very motivated, and they are very good at getting experts together,” said Xing.

Dr. Xing has been conducting multidisciplinary research mainly focused on structural biology, biochemistry, and system biology to understand protein phosphatase 2A regulation and disease mutations.

PP2A is critical for many cellular and physiological functions by the formation of ~100 heterotrimeric holoenzymes that belong to four major families. Multiple types of cancer and diverse neurological disorders are linked to the deregulation of PP2A.

The PP2R5D gene encodes one member of the regulatory subunits in the B’ family, known as B’d, making it an important part of the PP2A system. Her group initiated PPP2R5D research in 2017 under grant support from the Jordan’s Guardian Angels Foundation.

There are 12 different research groups across the United States and Europe that Jordan’s parents connected. All 12 research groups and Jordan’s parents attend bimonthly web meeting to discuss new progress and collaborations.

Jordan’s Guardian Angels Foundation has granted $1 million to the Xing lab since 2017 till 2021. They have raised money by fundraising and received support from the state of California, which works with UC Davis to distribute the grants to the different research groups.

The 12 research groups are studying the mutation from several angles such as stem cell research, animal models, cell biology, biochemistry, structural biology, and clinical work.

“The progress has been exceptional,” said Xing.

There can be several different ID mutations to PPP2R5D. The most common and most severe mutation is E198K and has been identified in the majority of patients with Jordan’s syndrome. More than 10 other PPP2R5D ID mutations have also been identified.

All mutations, except the mildest one that can be inherited, predominantly occur during spermatogenesis. Intriguingly, the same somatic mutations were found in the tumor tissue of cancer patients.

Each variation has similarities and shared symptoms with differences in severity. A deceased patient recently known to have a mild version of Jordan’s syndrome had been misdiagnosed for Parkinson’s disease for 20 years.

Using x-ray crystallography and single particle cryo-electron microscopy, the Xing lab is working to understand the unique conformation and structure of the wild type PP2A- B’d holoenzyme to ultimately understand how ID mutation in PPP2R5D changes the holoenzyme conformation.

“Our preliminary structural modeling suggests that mutations could alter enzyme conformation as well as substrate entry, a hypothesis under testing right now,” said Xing.

Building knowledge gained on substrate recognition, Xing’s lab has also built bioinformatic tools to predict PP2A substrates potentially affected by PPP2R5D ID mutations. For example, those in brain tissues such as the hippocampus, caudate nucleus, and cerebellum might contribute to the symptoms in learning, sleep, language, and sensor motor association.

“Built on structural understanding, we are also trying to understand how to restore the conformation of the mutant holoenzyme, and if we do that, hopefully we find a treatment for patients where we can identify small molecules that modulate the holoenzyme conformation,” said Xing.

The collaboration with the other research groups has been advantageous in moving forward with personalized medicine plans, and Dr. Xing is especially motivated by the potential to create effective treatment for the children living with Jordan’s Syndrome.

The foundation laid out a highway for personalized medicine for Jordan’s Syndrome, she said. Any potential therapeutic strategies could be rapidly tested and assessed in animal models and in vitro mini-brain of the disease established by other research groups.

Communicating with patient families and research teams has been exciting. “It is a good example for people to see how what you do in the lab can directly affect clinical practice and personalized medicine,” she said, “and the research on Jordan’s Syndrome also set up a great working model for tackling other phosphatase diseases that the lab research is involved.”