Researchers reveal new genetic mutation cause of childhood glaucoma

Researchers reveal new genetic mutation cause of childhood glaucoma

New genetic mutation may cause severe childhood cases glaucomaa debilitating disease that runs in families and can lead to vision loss in children as young as three years old, a study has found.

The discovery was made by an international team of researchers led by Mass Eye and Ear, a division of Mass General Brigham, and Boston Children’s Hospital and the results have been published in the Journal of Clinical Investigation.

Using advanced genome sequencing technology, researchers discovered a mutation in the thrombospondin-1 (THBS1) gene in three ethnically and geographically diverse families with childhood history of glaucoma. The researchers then confirmed their findings in a mouse model that had the genetic mutation and subsequently developed symptoms of glaucoma caused by a previously unknown disease mechanism.

The new findings could lead to better screening for childhood glaucoma and earlier, more targeted treatments to prevent vision loss in children who carry the mutation, according to the study authors.

“This is a very exciting discovery for families affected by childhood glaucoma,” said Janey L. Wiggs, MD, PhD, associate chief of clinical research in ophthalmology at Mass Eye and Ear and vice president of clinical research. in ophthalmology and Paul Austin Chandler Professor of Ophthalmology at Harvard Medical School. “With this new knowledge, we can offer genetic testing to identify children in a family who may be at risk for the disease and start disease surveillance and conventional treatments earlier to preserve their vision. In the future, we will seek to develop new therapies to target this genetic mutation.”

Leading cause of childhood blindness

Infantile, or congenital, glaucoma is a rare but serious disease that occurs in children from birth until the age of 3 years. Despite its rarity, childhood glaucoma is responsible for 5% of childhood blindness worldwide.

Glaucoma causes irreversible damage to the optic nerve of the eye, often due to the buildup of pressure inside the eye (intraocular pressure or IOP). In adults, this damage can occur over time without symptoms, which is why the condition is often referred to as a “sneaky stealer of sight.”

However, children and babies with childhood glaucoma can be born with severe disease and vision loss or lose vision later in childhood due to high IOP. This increase in pressure not only damages the optic nerve, but can also affect other structures in a child’s eye such as the cornea. Children with childhood glaucoma typically require surgery within the first three to six months of life, followed by several more operations throughout childhood.

With childhood glaucoma there is usually a strong hereditary component, often with several members of a family affected by the disease. According to Dr. Wiggs, by better understanding the genes involved, genetic testing can give affected families peace of mind about whether their child might be at risk of developing the disease.

Discover the genetic basis of the disease

For decades, researchers have turned to genetics to better understand the cause of glaucoma. When Dr. Wiggs began this line of research 30 years ago, scientists could only identify regions of the genome affected by glaucoma. Thanks to advances in genomic technology, researchers have been able to examine the full genetic makeup of individuals with and without glaucoma to determine which specific genetic mutations play a role in the disease. Research led by Dr Wiggs in 2021 used a dataset of more than 34,000 adults with glaucoma to identify 127 genes associated with the disease.

To better study genetic mutations in childhood glaucoma, Dr. Wiggs and his Mass Eye and Ear team first examined exome sequences from an American family of European-Caucasian descent who had been part of a project previous research and found a striking and novel variant. in thrombospondin-1, a well-known protein in the body involved in a number of important biological processes, such as the formation of new vessels (angiogenesis) and new tissues. This mutated gene has not been found in people without childhood glaucoma, nor in large population genetic databases. The mutation-modified amino acid has been evolutionarily conserved, indicating an important role in protein function. This finding led Dr Wiggs to contact colleagues at Flinders University in Australia to see if they had any families of childhood glaucoma with thrombospondin mutations. They surprisingly found two families with an alteration at the same amino acid: one of mixed European and Indian ancestry, and a Sudanese family originally from Africa.

“What was really striking about this finding was that these families all had this genetic variant, and it was not possible for them to be related because they came from such diverse backgrounds,” said Dr Wiggs. . “It meant there was something really important about this mutation.”

To further test this hypothesis, the researchers collaborated with Robert J. D’Amato, MD, PhD, Judah Folkman Chair in Surgery in the Vascular Biology Program at Boston Children’s Hospital and Professor of Ophthalmology at Harvard Medical School. . Dr. D’Amato’s team developed a mouse model with the THBS1 mutation and found that the mouse also showed features of glaucoma.

“Thrombospondin-1 is well known as a potent inhibitor of blood vessel growth or angiogenesis,” said Dr. D’Amato, who has studied angiogenesis for more than three decades. “I initially assumed that THBS1 mutations disrupted blood vessel formation in the eye, but our animal models showed normal angiogenesis. We realized there must be another mechanism.”

Specifically, D’Amato’s lab showed that the mutation caused the accumulation of abnormal thrombospondin proteins in the intraocular drainage structures of the eye involved in the regulation of IOP, which, in turn, led to an accumulation pressure that damaged the optic nerve and led to the loss of retinal ganglion cells, thus causing loss of vision.

It was the first time that researchers had identified this type of pathological mechanism responsible for childhood glaucoma.

“This work highlights the power of international collaborations,” said study co-author Owen M. Siggs MD, DPhil, associate professor at Flinders University and the Garvan Institute of Medical Research in Australia. “There is such incredible genetic diversity across the world, and comparing this information is becoming increasingly critical for findings like this.”

Personalized care for families with future study

The new study has important clinical implications, according to the researchers. Although there is still work to be done before comprehensive genetic testing can be offered, each gene found presents another opportunity to be able to identify the causative mutations in these families through screening, according to the authors.

Therapeutically, knowledge of this genetic mutation may lead to earlier treatments with conventional therapies. For example, if a baby is born with this mutation, their eye care specialist can better inform parents of the risks and develop a plan to monitor and treat the disease appropriately.

Identifying this new mechanism and gene behind childhood glaucoma could also lead to new therapies that target the accumulation of abnormal proteins. The researchers also aim to determine whether other THBS1 mutations are involved in the disease in adults, such as primary open-angle glaucoma, or milder forms of the disease if the mutation is not as pronounced.

Researchers will also continue to search for new genes associated with childhood glaucoma in the hope of one day developing a very comprehensive screening.

“Dr. Wiggs is an international expert in the genetics of glaucoma and has worked tirelessly to unravel the genetic contributions to these blinding diseases. These findings provide important insight into the causes of childhood glaucoma and offer the prospect of targeted therapy,” said Joan W. Miller. , MD, chair of ophthalmology at Mass Eye and Ear and Massachusetts General Hospital, Chief Ophthalmologist at Brigham and Women’s Hospital, and Chairman of Ophthalmology and David Glendenning Cogan Professor of Ophthalmology at Harvard Medical School. “This collaboration is a powerful demonstration of the power of translational research from bedside to bench to bedside, in uncovering disease pathogenesis and developing therapies for patients.


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