A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]

Abstract

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.

Figure 1

Pedigree structure of a family with autosomal dominant ataxia and haplotype reconstruction of chromosome 13q34 STR markers. Black symbols represent affected individuals; open symbols represent unaffected individuals. Question marks within symbols denote individuals with clinical status that is unknown because of either lack of data or uncertain diagnosis (see text). Black bars indicate a shared “risk” haplotype.

Figure 2

MRI of the brain of patient II:7 showed atrophy of cerebellar hemispheres (T1-weighted axial images).

Figure 3

A, Sequence electropherograms of mutations found in FGF14. Both normal (left) and mutated (right) DNA and amino acid sequences are shown. B (top), Amino acid sequence comparison of FGF11–FGF14 homologs in Homo sapiens, Mus musculus, and Gallus gallus, showing the conservation of the amino acid mutated in FGF14 (F145S) in the family with ataxia. The change of a phenylalanine to a serine in patients is indicated by an arrow. Only the alignment with amino acids 139–159 of FGF14 is shown. B (bottom), Amino acid sequence comparison around the mutated F145S for all FGFs found in Homo sapiens. Amino acid alignments were performed with ClustalW.

Figure 3C

Molecular models of wild-type and mutant FGF14. The purple and yellow ribbons correspond to α-helix and β-sheet structures, respectively. Indicated is the position of the wild-type (F145) (left panel) and mutated (Ser145) residue mutated in the family.