Hereditary spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders for which >/=14 different genetic loci have been identified. In some SCA types, expanded tri- or pentanucleotide repeats have been identified, and the length of these expansions correlates with the age at onset and with the severity of the clinical phenotype. In several other SCA types, no genetic defect has yet been identified. We describe a large, three-generation family with early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia, not associated with any of the known SCA loci, and a mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34. Our observations are in accordance with the occurrence of ataxia and paroxysmal dyskinesia in Fgf14-knockout mice. As indicated by protein modeling, the amino acid change from phenylalanine to serine at position 145 is predicted to reduce the stability of the protein. The present FGF14 mutation represents a novel gene defect involved in the neurodegeneration of cerebellum and basal ganglia.

Age of Onset, Amino Acid Sequence, Animals, Base Sequence, Chromosomes, Human, Pair 13/genetics, Female, Fibroblast Growth Factors/chemistry/*genetics, Genes, Dominant/*genetics, Genetic Predisposition to Disease/*genetics, Humans, Magnetic Resonance Imaging, Male, Mice, Models, Molecular, Molecular Sequence Data, Mutation/*genetics, Pedigree, Phenotype, Protein Conformation, Research Support, Non-U.S. Gov't, Spinocerebellar Ataxias/*genetics
hdl.handle.net/1765/8498
American Journal of Human Genetics
Erasmus MC: University Medical Center Rotterdam

van Swieten, J.C, Brusse, E, de Graaf, B.M, Krieger, E, van de Graaf, R, de Koning, I, … Heutink, P. (2003). A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. American Journal of Human Genetics. Retrieved from http://hdl.handle.net/1765/8498