A hidden gene finally explains this rare neurological disorder

The discovery, published in Nature Communications, helps explain a previously unsolved neurological disorder and offers new insight into how certain neurodegenerative diseases develop.

Researchers Link CD99L2 to Rare Neurological Disease

Before this study, CD99L2 was mainly recognized for its role in the immune system. No neurological function had been established for the gene.

Using a combination of genome-wide genetic analysis and laboratory experiments in cells, the research team demonstrated that CD99L2 is also essential for communication pathways within nerve cells. Their findings revealed that the gene plays a critical role in maintaining normal neuronal signaling.

How the Gene Affects Brain Cell Function

Scientists at Ruhr University Bochum found that the protein produced by CD99L2 works as an activating partner for CAPN1, a calcium-dependent protease already known to be involved in hereditary spastic paraplegia and ataxia.

"Disease-causing variants lead to disrupted production of the CD99L2 protein in the cell and prevent its interaction with CAPN1," explains Dr. Jonasz Weber. "Patients' cells also showed specific disruptions of synaptic processes."

According to the researchers, defects in CD99L2 reduce the activation of CAPN1. This, in turn, disrupts important neuronal signaling pathways, providing a likely explanation for the movement-related symptoms seen in affected patients.

Combining Genetics and Neuroscience

The findings highlight the value of combining genetic testing with functional studies of how genes operate inside cells.

"Our results show that genetic diagnostics and functional neuroscience are not mutually exclusive areas," says Weber. "Only when both disciplines work closely together can a reliable disease mechanism be derived from a genetic variant."

Identifying CD99L2 as a disease-causing gene could improve genetic diagnosis for people with rare movement disorders. It also provides researchers with new information about the biological processes involved in neurodegeneration.

What Is Spastic Ataxia?

Spastic ataxia is a group of rare neurodegenerative disorders characterized by problems with movement coordination (ataxia) together with spastic paralysis. The symptoms result from damage affecting the cerebellum and motor pathways within the central nervous system.

The age at which symptoms appear and the progression of the disease can vary widely depending on the underlying genetic cause.

The large-scale genetic analysis of the patient cohort was carried out in Tübingen under the supervision of Dr. Tobias Haack. Functional studies of the newly identified disease gene were led by Dr. Jonasz Weber and colleagues at the Department of Human Genetics at Ruhr University Bochum.