Identification of the Genetic Causes Underlying Spinocerebellar Ataxia 11 and Brown-Vialetto-Van Laere Syndrome

The Spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by lack of coordination of gait and limb movements due to progressive degeneration of the cerebellum and its afferent and efferent connections. Thirty loci have been described in publications to date with just over half of the responsible genetic lesions discovered. Here we describe our finding that spinocerebellar ataxia type 11 is caused by mutations in the gene encoding Tau Tubulin Kinase 2. This is the first time that a genetic defect of a Tau kinase has been shown to cause neurodegeneration. This is also the first time a spinocerebellar ataxia has been linked to defects in a gene associated with Tau regulation or deposition. Spinocerebellar ataxia (SCA) is caused by several mechanisms including dynamic mutations, static mutations, and structural changes. SCA15 and SCA20 are caused by structural changes; we therefore considered that structural variation might account for novel ataxia subtypes. We screened 188 spinocerebellar ataxia patient DNA samples for structural changes, and identified SCA32 in a family from Northern France. SCA32 is associated with a 7.5Mb duplication at chromosome 11q21-11q22.3. We also investigate a very different neurodegenerative disease. BrownVialetto-van Laere syndrome (BVVL), or progressive pontobulbar palsy with deafness, is an extrememly rare disorder characterized by a variety of cranial nerve palsies and progressive sensorineural hearing loss. Only approximately 60 cases have been described in the literature since 1894. Here we utilize autozygosity mapping, genotyping arrays and next generation sequencing to find genetic causes of BVVL. Our data suggests that there is more than one genetic lesion underlying this condition.