Gene Mutation Leads to Early Childhood Neurodegenerative Disorder, Researchers Find

Researchers found that inherited mutations in the PMPCB gene lead to a wide range of impairments in mitochondria and cause a form of early childhood neurodegenerative disorder in members of four unrelated families.

The study, “Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood,” was published in The American Journal of Human Genetics.

Problems in mitochondrial function due to genetic mutations are linked to diseases in high-energy demanding organs, such as the brain, heart, or skeletal muscles. But the genetic defects can be diverse.

Now, a team of researchers from Germany was able to identify a variant in a specific gene called PMPCB in members of four unrelated families on three different continents.

The PMPCB gene provides instructions for a subunit of a protein called MPP (mitochondrial presequence protease) that is required for a healthy mitochondrial function. Specifically, this protein removes sequences called presequences that are embedded in proteins and targeted for mitochondria, allowing proteins to enter a mature state.

Researchers found that all individuals affected by an impaired MPP function had features of Leigh syndrome, a severe neurological disorder. They have lesions on the brain’s basal ganglia cells that govern motor control, motor learning, executive functions and behaviors, and emotions. Patients also showed prominent cerebellar atrophy.

Mutations in the PMPCB gene led to defective functioning of the MPP protein, which was no longer capable of cleaving the presequences efficiently, leading to the accumulation of immature proteins inside mitochondria. This accumulation affects several mitochondrial functions.

“Given the crucial role of MPP in processing 70% of all mitochondrial precursor proteins, dysfunction of MPP was long considered to be incompatible with life as it profoundly interferes with mitochondrial homeostasis,” researchers wrote.

They introduced the defective gene versions in yeast, a popular research model organism, which led to severe growth defects and impairments in mitochondria function.

“The yeast model revealed significant defects in the mitochondrial biosynthesis of iron-sulfur clusters, which are indispensable for many cellular functions including mitochondrial bioenergetic processes, nuclear genome maintenance, and cytosolic protein translation,” they wrote.

The analysis of biopsy materials of an affected children also showed significant defects in mitochondria.

Overall, these results show that inherited mutations in the PMPCB gene are linked to a complex form of neurodegeneration in early childhood.

“Sadly we have not yet been able to save any of the sick children with our findings,” Dr. Nora Vögtle, group leader at the Institute of Biochemistry and Molecular Medicine of the University of Freiburg, Germany and the study’s lead author, said in a press release.

“However without this fundamental explanation of pathological mechanisms no therapeutic approaches could be developed. We hope that our work will lead to the development of effective therapies in the long term,” she said.