One in 8 Billion: Unique Gene Mutation Causes Retinal Disease

Macro shot of mid 20's brown eyed woman having her eyes examined at optometrists office
Article Summary
  • Dr. Pankaj Agrawal and colleagues are studying mutations in the HBS1L gene.
  • To Dr. Agrawal’s knowledge, the mutation only affects one person in the world.
  • The HBS1L mutation is causing retinal dystrophy and other issues for that one person.

Researchers at the University of Miami Miller School of Medicine, Boston Children’s Hospital and the Manton Center for Orphan Disease Research have shown that mutations in the HBS1L gene disrupt eye function and cause retinal dystrophy.

The study was published in the journal Disease Models and Mechanisms.

“As far as we know, the mutations in this specific gene affect only one person in the world,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the Miller School Department of Pediatrics and Jackson Health System. “We have spent more than 10 years trying to understand how recessive loss of function variants in HBS1L influence this patient’s condition, and it is giving us a greater understanding of how proteins are made and what can go wrong.”

Ribosomes are the molecular machines that help convert messenger RNA into proteins and are essential in virtually all human cells. When they go awry, HBS1L and other rescue proteins recycle their component molecules to prevent unhealthy proteins.

“Anytime protein translation happens, there are errors that may accumulate,” said Dr. Agrawal. “There has to be a mechanism, on the cellular level, that fixes those errors. This is one of those proteins and when it’s mutated, that can cause serious problems.”

Miller School of Medicine pediatrician Dr. Pankaj Agarwal
Dr. Pankaj Agrawal is studying a rare gene mutation to learn more about how proteins are made.

For the patient with HBS1L deficiency, this systemic ribosomal dysfunction is causing vision problems, delayed development, low muscle tone and other issues. Dr. Agrawal and colleagues published two previous papers, in Blood and PLoS Genetics, that explored other ways HBS1L dysfunction is affecting her biology. In this study, they investigated the gene’s relationship with retinal dystrophy, a degenerative eye disorder.

A Multi-omics Study

The team took a multi-omics approach, studying the patient’s DNA, RNA and proteins, as well as those in an animal model, to illuminate how ribosome rescue protein dysfunction is causing the patient’s symptoms. They found that HBS1L mutations changed how hundreds of proteins are expressed, increasing 169 while decreasing 480.

They found decreases in rhodopsin and peripherin 2, two important proteins for retinal function. This fits well in the biological puzzle, as HBS1L is normally highly expressed in and around the retina. Those results were confirmed in the animal model.

These findings are helping scientists understand how HBS1L defects are driving this patient’s eye issues, as well as ribosomal disorders more generally.

“This one patient has given us great insight into the function of this protein and how ribosomal rescue happens and how critical HBS1L is to this process,” said Dr. Agrawal. “It’s really helping us understand the biology.”

Tags: Dr. Pankaj Agrawal, genetics, neonatology