Miller School Expertise Plays Pivotal Role in International Whole Exome Study

Miller School researchers co-led an international study that identifies a new genetic syndrome associated with complex hereditary spastic paraplegia (HSP), a condition characterized by slowly progressing spasticity in the legs that can lead to severe disability. Led by Stephan Züchner, M.D., Ph.D., professor and Interim Chair of the Dr. John T. Macdonald Foundation Department of Human Genetics, researchers at the Miller School made the discovery possible by lending their widely recognized expertise in computing and interpreting whole exome data.

Published online first in the June 6 issue of the American Journal of Human Genetics, the study, “Alteration of Ganglioside Biosynthesis Responsible for Complex Hereditary Spastic Paraplegia,” also solidifies the alteration of lipid metabolism as the cause of HSP.

In the study, researchers identified mutations in B4GALNT1 using whole-genome linkage mapping and exome sequencing to analyze 18 HSP-affected patients from seven unrelated families in Europe, Spain and North Africa, underscoring the widespread scope of the disease.

“The identification of B4GALNT1 is another example of increasing the pace of discovery by collaborative analysis of ‘big data,’” said Züchner, co-senior author. “This is the sixth novel disease gene we identified in the past six months with this wonderful group of collaborators.”

Several of these recent genetic studies suggest that the balance of specific lipids in the brain plays a significant role in the development of diseases like HSP.

“We hope that such insight will lead to a focused development of new therapeutic options,” said Züchner, noting that no treatment is available to prevent or slow HSP.

Other Miller School contributors include Michael A. Gonzalez, Ph.D. student; Fiorella Speziani, project manager of research support; and Rafael F. Acosta Lebrigio, senior systems analyst.

The study is a collaborative effort with investigators from 17 universities and research institutions in the United States, Tunisia, France, Germany, Portugal, Brazil, and Canada. In addition to Züchner, the research was co-led by Giovanni Stevanin, Ph.D., research director at INSERM and professor at the École Pratique des Hautes Etudes in Paris.

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