A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia

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.

Functional evolutionary history of the mouse Fgf gene family

“…FGF20 is a potential risk factor for Parkinson's disease (van der Walt et al, 2004;Satake et al, 2007). FGF13 is a candidate gene for Börjeson-Forssman-Lehmann syndrome (Gecz et al, 1999) and a hereditary spinocerebellar ataxia syndrome (SCA27) is caused by mutations in FGF14 (van Swieten et al, 2003;Dalski et al, 2005).…”

Fibroblast growth factor homologous factors: Evolution, structure, and function

“…In humans, spinocerebellar ataxia (SCA) is a genetically inherited syndrome, and many different SCA loci have been genetically mapped. One SCA locus spans the FHF4 gene, and coding missense or frameshift mutations have been identified in a few families transmitting SCA (Dalski et al, 2005;van Swieten et al, 2003). The third Fhf4 −/− phenotype is muscle weakness, as manifested by reduced ability to hang on to tilted or inverted grids and reduced climbing ability.…”

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families

“…To date, 29 different genetic loci have been reported to be responsible for ADCA (http://www.gene.ucl.ac.uk/cgi-bin/nomenclature): spinocerebellar ataxia type 1 (SCA1) on chromosome 6p22-p23 (Orr et al 1993); SCA2 on 12q23-q24.1 (Imbert et al 1996;Sanpei et al 1996); Machado-Joseph disease (MJD)/ SCA3 on 14q24.3-q32.1 (Kawaguchi et al 1994); SCA4 on 16q22.1 (Flanigan et al 1996); SCA5 on 11q13.2 (Ranum et al 1994); SCA6 on 19p13.1 (Zhuchenko et al 1997); SCA7 on 3p12-p13 (David et al 1997); SCA8 on 13p (Koob et al 1999); SCA10 on 22q13-qter. (Matsuura et al 2000); SCA11 on 15q14-q21.3 (Worth et al 1999); SCA12 on 5q31-33 (Holmes et al 1999);SCA13 on 19q13.3-q13.4 (Waters et al 2006); SCA14 on 19q13.42 Chen et al 2003;Yabe et al 2003); SCA15 on 3p24.2 (Gardner et al 2005); SCA16 on 8q23-q24.1 (Miyoshi et al 2001); SCA17 on 6q27 (Nakamura et al 2001); SCA18 on 7q22 (Brkanac et al 2002); SCA19 on 1p21-q21 (Verbeek et al 2002); SCA20 on 11p11.2-q13.3 (Knight et al 2004); SCA21 on 7p21.3-p15.1 (Vuillaume et al 2002); SCA22 on 1p21-q23 (Chung et al 2003); SCA23 on 20p13-p12 (Verbeek et al 2004); SCA24 on 1p26 (Swartz et al 2002); SCA25 on 2p21-p15 (Stevanin et al 2004); SCA26 on 19p13.3 (Yu et al 2005); SCA27 on 13q33.1 (Van Swieten et al 2003); SCA28 on 18p11.22-q11.2 (Cagnoli et al 2006); SCA 29 on 3p26 (Dudding et al 2004) and dentatorubral pallidoluysian atrophy (DRPLA) on 12p13.31 (Koide et al 1994;Nagafuchi et al 1994). Among these loci, causative genes have been further identified containing trinucleotide repeats (CAG) in S...…”

“…On the other hand, deletion and/or point mutations were identified in the SPTBN2, KCNC3, PRKCG, and FGF14 genes, recently attributed to SCA5, SCA13, SCA14, and SCA27 respectively Waters et al 2006;Yamashita et al 2000;Chen et al 2003;Yabe et al 2003;Van Swieten et al 2003). Point mutations may result in decreased stability of the proteins, and frameshift mutations in truncated proteins (Van Swieten et al 2003;Dalski et al 2005).…”

“…Point mutations may result in decreased stability of the proteins, and frameshift mutations in truncated proteins (Van Swieten et al 2003;Dalski et al 2005). More recently, single nucleotide substitutions have been identified in the puratrophin-1 and contactin 4 (CNTN4) genes, classified as 16q-linked ADCA and SCA16 respectively (Takashima et al 2001;Li et al 2003;Mizusawa et al 2004;Ishikawa et al 2005;Miura et al 2006).…”