Rare movement disorder linked to CD99L2 gene variants
Researchers say mutations in CD99L2 explain cases of X-linked spastic ataxia and reveal a role for the gene in nerve-cell signaling.
By Lucas Ferreira · Science & Environment Writer
3 min read
Researchers in Germany have identified harmful variants in the gene CD99L2 as a cause of X-linked spastic ataxia, a rare movement disorder involving impaired coordination and spastic paralysis. Ruhr-University Bochum said the finding may help diagnose patients whose neurological conditions have remained genetically unexplained.
The work, published in Nature Communications, drew on genetic data from 2,811 people with ataxia, hereditary spastic paraplegia and dystonia, according to Ruhr-University Bochum. The university said the analysis linked loss-of-function variants in CD99L2 to the disorder, expanding the gene’s known role beyond the immune system.
A gene with a new neurological role
Before the study, CD99L2 was mainly associated with immune function, Ruhr-University Bochum said. The research team reported that laboratory studies in cells showed the gene also helps maintain communication processes inside nerve cells.
The scientists found that the protein made by CD99L2 acts as an activating partner for CAPN1, according to the university. CAPN1 is a calcium-dependent protease that had already been connected to hereditary spastic paraplegia and ataxia.
Ruhr-University Bochum said disease-causing CD99L2 variants interfere with production of the CD99L2 protein and stop it from interacting normally with CAPN1. The researchers also reported disruptions in synaptic processes in patient cells.
According to the study team, reduced activation of CAPN1 offers a likely explanation for how CD99L2 defects disturb neuronal signaling pathways. The university said those cellular changes fit with the movement symptoms seen in affected patients.
Large-scale genetics paired with cell studies
The patient analysis was carried out in Tübingen under the supervision of Dr. Tobias Haack, Ruhr-University Bochum said. Functional studies of the gene were led by Dr. Jonasz Weber and colleagues in the Department of Human Genetics at Ruhr University Bochum.
Weber said the findings show that genetic diagnostics and functional neuroscience need to work together to establish a disease mechanism from a genetic variant, according to the university. The study combined genome-wide genetic analysis with experiments designed to test how the gene functions in cells.
The researchers said identifying CD99L2 as a disease-causing gene could improve genetic diagnosis for people with rare movement disorders. Ruhr-University Bochum also said the finding gives scientists another route to study biological processes involved in neurodegeneration.
What spastic ataxia involves
Ruhr-University Bochum described spastic ataxia as a group of rare neurodegenerative disorders marked by ataxia, or problems with movement coordination, along with spastic paralysis. The university said the symptoms stem from damage affecting the cerebellum and motor pathways in the central nervous system.
The age at which symptoms begin and how quickly the disease progresses can vary depending on the genetic cause, according to the university. The newly reported CD99L2 link adds one more explanation for cases that previously lacked a clear molecular diagnosis.
The Nature Communications paper is titled “Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia,” according to the journal reference provided by Ruhr-University Bochum.
This story draws on original reporting from ScienceDaily.