The purpose of this research program is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. Specific research accomplishments in the past year include (1) characterization of a patient with Sandhoff disease and SH3TC2 deficiency, (2) identification of mutation in CPT1C in a family with spastic paraplegia (HSP). Sandhoff disease is a lysosomal storage disease caused by a deficiency of beta-hexosaminidase. Affected individuals present with a wide spectrum of clinical manifestations, ranging from psychomotor impairment and death in the infantile form to motor neuron disease and autonomic dysfunction in the adult form We identified a family with predominantly sensory neuropathy that was found to have both Sandhoff disease and deficiency of SH3TC2. We examined and followed up with a family presenting for evaluation of HSP. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the number and size of lipid droplets on overexpression in cells. We also observed a reduction of lipid droplets in primary cortical neurons isolated from Cpt1c−/− mice as compared with wild-type mice, suggesting a dominant negative mechanism for the mutation. This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.
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| Grunseich, Christopher; Schindler, Alice B; Chen, Ke-Lian et al. (2015) Peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency. J Neurol 262:1066-8 |
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