Global team of scientists discover new gene causing severe neurodevelopmental delay

An international team of researchers led by UC Davis geneticist Suma Shankar has discovered a new gene involved in a neurodevelopmental condition called DPH5-associated diphtamide deficiency syndrome. This syndrome is caused by a variant of the DPH5 gene that can cause embryonic death or profound neurodevelopmental delay.

Findings from their study were published in Genetics in Medicine.

“We are very excited about the discovery of this new gene,” said lead author Suma Shankar, professor in the Department of Pediatrics and Ophthalmology and faculty at the UC Davis MIND Institute. Shankar is 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 the class of genes required for the synthesis of diphtamide, a type of modified amino acid histidine, essential for the synthesis of ribosomal proteins.

“We provide strong clinical, biochemical and functional evidence for DPH5 as a major cause of embryonic death and neurological dysfunction. Disruption to the work of DPH5 impacts many systems and organs of the body, including the heart,” says Shankar.

Parents with the DPH5 variant now know that the odds of having a child with this disorder are one in four. They can choose to have prenatal genetic testing before or during pregnancy.” -Suma Shankar

Collaboration sparks discovery

UC Davis is leading this project, with collaborations from around the world. Scientists from Germany, Saudi Arabia, Sweden, Massachusetts, and California are working together to uncover this new gene.

The project started with an office visit. In 2018, Shankar saw a Syrian family with two children exhibiting severe neurodevelopmental delay at a precision genomics clinic. Blood related parents are interested in genetic testing to understand what causes their children’s symptoms. Analysis revealed one specific gene, DPH5 with ‘variance of uncertain significance’.

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

In total, the study found specific DPH5 variants in five children exhibiting neurodevelopmental delay. The youngest is 11 days and the oldest is 10 years. Three girls and two boys. They have distinct head and facial features, severe disabilities, heart defects and difficulty eating.

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

Developed the DPH5 . mouse model

As soon as Shankar and team discovered the gene variant in the first family, they started working on a targeted mouse model. In collaboration with the UC Davis Mouse Biology Program, they developed a model with changes mimicking the DPH5 gene found in the first family.

The DPH5 variant in both copies of the gene in the mouse model proved lethal. Only one mouse was born alive but died 24 days later. It exhibits impaired growth, head and facial deformation, and multisystem dysfunction, similar to humans.

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

Testing for variants in human and yeast cells

Model of the human DPH5 variant and its interaction with eEF2.

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

In addition, the team worked with Swedish experts to carry out computer simulation modeling of the variants. Simulations show the altered structure of DPH5 and its impaired interaction with eEF2, a protein essential for the synthesis of other proteins.

Research that supports family decision making

This study expands the knowledge of diphtamide deficiency syndrome and diseases related to ribosomal protein production. In an era of precision medicine and targeted therapy, knowing the underlying genetic causes of disease can have an impact on the treatment of individuals with neurodevelopmental delay.

“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.

Studies show that it is an autosomal recessive disorder. This means both parents must carry the gene mutation to have a child with the DPH5-related condition.

“Parents with the DPH5 variant now know that the odds of having a child with this disorder are one in four. They may choose to have prenatal genetic testing before or during pregnancy,” says Shankar.

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

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