Global team of scientists discovers new gene that causes severe neurodevelopmental delays

An international team of researchers led by UC Davis geneticist Suma Shankar has discovered a new gene implicated in a neurological disorder called DPH5-related diftamide deficiency syndrome. The syndrome is caused by DPH5 gene variants that can lead to embryonic death or severe neurodevelopmental delays.

The findings of their study were published in Genetics in Medicine.

“We are so excited about the discovery of new genes,” said lead author Suma Shankar, a professor in the Departments of Pediatrics and Ophthalmology and faculty at the UC Davis MIND Institute. Shankar is the Director of Precision Genomics, Albert Rowe Endowed Chair in Genetics, and Head of the Division of Genomic Medicine.

DPH5 is essential for protein biosynthesis. It belongs to a class of genes required for the synthesis of diphtamide, a type of modified amino acid histidine essential for ribosomal protein synthesis.

“We provide strong clinical, biochemical and functional evidence for DPH5 as a cause of embryonic death and severe neural dysfunctions. Disruption to the work of DPH5 affects multiple body systems and organs, including the heart,” Shankar said.

Suma Shankar

Parents with DPH5 variants now know that the chance of having a child with the disorder is one in four. They may choose to perform prenatal genetic testing before or during pregnancy. “-Suma Shankar

Collaborations lead to discoveries

UC Davis led this project, with collaborations from around the world. Scientists from Germany, Saudi Arabia, Sweden, Massachusetts and California worked together to discover this new gene.

The project started with an office visit. In 2018, Shankar saw a Syrian family with two children with severe neurodevelopmental delays in the precision genomics clinic. The consanguineous parents were interested in genetic testing to understand what was causing their children’s symptoms. The analysis revealed one specific gene, DPH5, to be a ‘variant of uncertain significance’.

Shankar posted the variant on the GeneMatcher website to try and find other families with DPH5 variants. The program identified two families: one in Massachusetts and the other in Riyadh, Saudi Arabia. The Undiagnosed Disease Network program had performed genome sequencing for the family in Massachusetts.

In all, the study discovered specific DPH5 variants in five children with neurodevelopmental delays. The youngest was 11 days old and the oldest was 10. Three were female and two were male. They had distinct head and facial features, severe disabilities, abnormalities in their hearts and nutritional problems.

“We could say that the changes in the gene are likely disease-causing variants,” Shankar said.

Developing a DPH5 mouse model

Once Shankar and the team found the gene variant in the first family, they set to work with a targeted mouse model. In collaboration with the UC Davis Mouse Biology Program, they developed a model with an altered DPH5 gene that mimics the changes found in the first family.

The DPH5 variant on both copies of the gene in the mouse model was found to be lethal. Only one mouse was born alive, but died 24 days later. It showed reduced growth, head and face deformity, and multisystem dysfunction, similar to that seen in humans.

“We had to make different mouse models with different generations. Still, we were able to develop only one very small mouse with clear craniofacial features,” Shankar said.

Testing the variant in human and yeast cells

Twisted gold and gray strands representing a DPH5 variant model interacting with the eEF2 model in green
Model of human DPH5 variants and their interaction with eEF2.

The team also studied the effects and interactions of the DPH5 variants in human and yeast cells. Working with researchers from Roche in Germany, they found that DPH5 variants in human and yeast cells led to absent or low DPH5 function.

In addition, the team collaborated with Swedish experts to perform computer simulation modeling of the variants. The simulations showed an altered DPH5 structure and disruption of its interaction with eEF2, a protein essential for other protein synthesis.

Research to support family decisions

The study expands knowledge on diftamide deficiency syndromes and diseases related to ribosomal protein production. In the age of precision medicine and targeted therapies, knowing the underlying genetic causes of the disease can influence the care of individuals with such neurodevelopmental delays.

“Now we can start thinking about studies to better understand the physiology of the disease and to determine the function of the DPH5 gene,” Shankar said.

The study found that this is an autosomal recessive disorder. It means that both parents must carry the gene mutation to have a child with a DPH5-related condition.

“Parents with DPH5 variants now know that the chance of having a child with the condition is one in four. They can choose to have prenatal genetic testing before or during pregnancy,” Shankar said.

This research was supported by National Institutes of Health (NIH) grants (U01HG007690, U42 OD012210) and DFG Priority Program 1927 ‘Iron-Sulphur for Life’ and Children’s Miracle Network grant in Pediatric Genetics.

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