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A Loss-of-Function Disease Mechanism?

Joanna C. Bakowska, PhD; Heng Wang, MD, PhD; Baozhong Xin, MD, PhD; Charlotte J. Sumner, MD; Craig Blackstone, MD, PhD

Arch Neurol. 2008;65(4):520-524.

Background  Hereditary spastic paraplegias (SPG1-SPG33) are characterized by progressive spastic weakness of the lower limbs. A nucleotide deletion (1110delA) in the (SPG20; OMIM 275900) spartin gene is the origin of autosomal recessive Troyer syndrome. This mutation is predicted to cause premature termination of the spartin protein. However, it remains unknown whether this truncated spartin protein is absent or is present and partially functional in patients.

Objective  To determine whether the truncated spartin protein is present or absent in cells derived from patients with Troyer syndrome.

Design  Case report.

Setting  Academic research.

Patients  We describe a new family with Troyer syndrome due to the 1110delA mutation.

Main Outcome Measures  We cultured primary fibroblasts and generated lymphoblasts from affected individuals, carriers, and control subjects and subjected these cells to immunoblot analyses.

Results  Spartin protein is undetectable in several cell lines derived from patients with Troyer syndrome.

Conclusions  Our data suggest that Troyer syndrome results from complete loss of spartin protein rather than from the predicted partly functional fragment. This may reflect increased protein degradation or impaired translation.

Author Affiliations: Cellular Neurology Unit (Drs Bakowska and Blackstone) and Neurogenetics Branch (Dr Sumner), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and DDC Clinic for Special Needs Children, Middlefield, Ohio (Drs Wang and Xin). Dr Bakowska is now with the Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois. Dr Sumner is now with the Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.