Exome Sequencing Doubles Known Genetic Causes of Hereditary Spastic Paraplegia and Reveals Links to Common Neurodegenerative Diseases

Summary

An international team led by researchers at the University of California, San Diego School of Medicine reports a major advance in understanding hereditary spastic paraplegia (HSP). Published in Science (January 31, 2014), the study doubles the number of genes known to cause HSP, a group of neurodegenerative disorders characterized primarily by progressive stiffness and weakness of the lower limbs. HSP can also present with epilepsy, cognitive impairment, blindness and other neurological features. The work identifies numerous previously unknown genetic causes and maps how these genes interact, providing new insight into biological pathways that overlap with more common neurodegenerative diseases.

Study design and key findings

Over several years, UC San Diego investigators assembled the largest reported cohort to date of families affected by autosomal recessive HSP. Focusing on regions and populations with higher rates of consanguinity or shared ancestry, the team recruited more than 50 families and analyzed roughly 100 affected individuals. Using whole exome sequencing—a technique that reads the protein-coding portions of the genome—they identified a likely genetic cause in almost 75 percent of cases. Remarkably, about half of those disease-causing mutations were located in genes not previously linked to any human disorder.

Finding so many novel genetic causes allowed the researchers to take a systems-level view. They constructed what they call the “HSP-ome”—a network map that integrates newly discovered genes with those already known to cause HSP. This interactome not only helped validate additional mutations among study participants, but also highlighted key biological pathways implicated in HSP. Those pathways point to cellular processes and molecular mechanisms that appear to overlap with other neurodegenerative conditions.

Implications for neurodegeneration research and treatment development

One of the most consequential observations from the study is that the HSP-ome connects hereditary spastic paraplegia with more common neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). That link suggests shared biological processes across seemingly distinct diseases and supports the idea that insights gained from rare, genetically defined disorders can illuminate mechanisms relevant to broader neurodegenerative research.

According to senior author Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator and professor in the UC San Diego departments of Neurosciences and Pediatrics, understanding the underlying biological processes is essential for guiding future research aimed at identifying precise disease mechanisms and developing effective therapies. Co-lead authors Gaia Novarino, PhD, and Ali G. Fenstermaker emphasize that combining genomic analysis in carefully selected patient populations with network approaches is a powerful strategy for expanding our knowledge of disease causes and prioritizing molecular targets for treatment development.

Collaborations and contributors

This project was highly collaborative, involving clinicians and researchers from numerous institutions and countries. Co-authors include specialists from Egypt, Turkey, Iran, Jordan, Saudi Arabia, Qatar, Morocco, India, Pakistan, France, the United States and other centers. Contributors ranged from clinical geneticists and pediatric neurologists to computational biologists and international research teams who provided samples, patient assessments and analytical expertise.

Funding and support

Funding for the research was provided in part by major scientific agencies and foundations, including the Deutsche Forschungsgemeinschaft, the Brain & Behavior Research Foundation (BBRF), and several National Institutes of Health grants (R01NS041537, R01NS048453, R01NS052455, P01HD070494 and P30NS047101). Additional support came from the French National Agency for Research, the Verum Foundation, the European Union, Fondation Roger de Spoelberch, Investissements d’avenir and the Princess Al Jawhara Center of Excellence in Research of Hereditary Disorders.

Contact and citations

Contact: Scott LaFee – UCSD

Source: UCSD press release

Original Research: “Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders” by Gaia Novarino, Ali G. Fenstermaker, Maha S. Zaki, Matan Hofree and colleagues. Science. Published online January 30, 2014. DOI: 10.1126/science.1247363.

#genetics #neurodegeneration