An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains.
Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia (chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C-->T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called "puratrophin-1" (Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1--normally expressed in a wide range of cells, including epithelial hair cells in the cochlea--was aggregated in Purkinje cells of the chromosome 16q22.1-linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region (UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Yushima, Tokyo, Japan.
Kinya
K
Ishikawa
Shuta
S
Toru
Taiji
T
Tsunemi
Mingshun
M
Li
Kazuhiro
K
Kobayashi
Takanori
T
Yokota
Takeshi
T
Amino
Kiyoshi
K
Owada
Hiroto
H
Fujigasaki
Masaki
M
Sakamoto
Hiroyuki
H
Tomimitsu
Minoru
M
Takashima
Jiro
J
Kumagai
Yoshihiro
Y
Noguchi
Yoshiyuki
Y
Kawashima
Norio
N
Ohkoshi
Gen
G
Ishida
Manabu
M
Gomyoda
Mari
M
Yoshida
Yoshio
Y
Hashizume
Yuko
Y
Saito
Shigeo
S
Murayama
Hiroshi
H
Yamanouchi
Toshio
T
Mizutani
Ikuko
I
Kondo
Tatsushi
T
Toda
Hidehiro
H
Mizusawa
D020121:5' Untranslated Regions; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D002885:Chromosomes, Human, Pair 16; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D005192:Family Health; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006056:Golgi Apparatus / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000502:physiology; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007438:Introns; D018895:Microsatellite Repeats; D008957:Models, Genetic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013049:Spectrin / Q000235:genetics* / Q000502:physiology; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D014018:Tissue Distribution; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D020121:5' Untranslated Regions; D000906:Antibodies; D017931:DNA Primers; D005819:Genetic Markers; D020662:Guanine Nucleotide Exchange Factors; C503982:PLEKHG4 protein, human; D012333:RNA, Messenger; D013049:Spectrin; D020741:rho GTP-Binding Proteins