Mutations in GEMIN5 protein can cause rare genetic disorders in children

An international team of collaborating researchers led by scientists at UPMC Children’s Hospital of Pittsburgh has discovered a genetic cause of an unusual neurological disorder characterized by developmental delay and loss of coordination, known as ataxia. The study was reported in a paper published recently in Nature Communications.

Udai Pandey, PhD, Associate Professor of pediatrics, human genetics and neurology, University of Pittsburgh School of Medicine. Image Credit: University of Pittsburgh Medical Center.

Scientists discovered that the condition is caused by mutations in a protein named GEMIN5, which is one of the primary building blocks of a protein complex that regulates RNA metabolism in neurons. GEMIN5 mutations have not previously been related to any genetic disorder.

It’s just like building a house. You take out the most important brick at the base and the whole building falls apart.”

Udai Pandey, PhD, Study Senior Author and Associate Professor, Pediatrics, Human Genetics and Neurology, University of Pittsburgh School of Medicine

GEMIN5 is a component of a protein complex that controls a variety of critical cellular processes, such as the development of specialized outgrowths from nerve cells known as axons and dendrites. Intriguingly, mutations in another main protein of the complex, known as survival motor neuron protein, result in a distinct devastating disorder, that is, spinal muscular atrophy.

To collect evidence for the study, Pittsburgh researchers called pediatricians, neurologists, and geneticists from all over the world, finally gathering information from 30 patient families from 12 different countries.

Since isolating live neurons from humans is impossible, researchers had to devise a different method of obtaining samples for future study.

They obtained blood samples from pediatric patients with undiagnosed neurological symptoms who were sent to neurogenetic clinics. Blood samples were first collected to isolate cells, which were then reprogrammed into neurons in the lab with cautious tinkering.

Scientists connected neurologic symptoms of the disorder to 26 mutations in the GEMIN5 gene that triggers disruption to the protein’s structure after matching genetic material from reprogrammed neurons from ill children with that of unaffected relatives.

Children came into the clinic with non-specific symptoms, such as developmental delay and abnormal gait. Their doctors ran all the possible tests, including assessing a child’s metabolic function, to no avail—their conditions had no easy explanation. It was not until we did an extensive genome analysis that we found that these patients had mutations in the GEMIN5 gene.”

Deepa Rajan, MD, Study Co-First Author and Assistant Professor, Pediatrics, Pitt School of Medicine

“Many genetic disorders seem individually rare, but collectively they are relatively common. We now are able to harness next-generation technology to help diagnose previously undiagnosed children, and each new gene discovery is the start of the journey to understanding each of these diseases better,” said Rajan, who works as a neurologist and also serves as the Neurogenetics Clinic director at UPMC Children’s Hospital.

Additional studies established a stronger correlation between GEMIN5 protein damage and disease manifestations. Scientists discovered that depleting an analog of human neuronal GEMIN5 protein in fruit flies was fatal if done early in the fly’s life cycle, or significantly delayed its development if such disruption occurred later.

The most exciting part of being a researcher is working on a project that directly helps families. We are hopeful that because of our study, neurologists will now consider testing for GEMIN5 mutations and that labs will include GEMIN5 in their testing for ataxic disorders. Genetic diseases are challenging to identify and treat, but if we find a cure, it will make a massive difference in someone’s life.”

Udai Pandey, PhD, Study Senior Author and Associate Professor, Pediatrics, Human Genetics and Neurology, University of Pittsburgh School of Medicine