Neurogenetics (2004) 5:215–221 DOI 10.1007/s10048-004-0194-z ORIGINAL ARTICLE Ryuki Hirano · Hiroshi Takashima · Ryuichi Okubo · Keiko Tajima · Yuji Okamoto · Shimon Ishida · Kazuhito Tsuruta · Takayo Arisato · Hitoshi Arata · Masanori Nakagawa · Mitsuhiro Osame · Kimiyoshi Arimura Fine mapping of 16q-linked autosomal dominant cerebellar ataxia type III in Japanese families Received: 1 June 2004 / Accepted: 16 August 2004 / Published online: 29 September 2004  Springer-Verlag 2004 Abstract The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. To date, at least 11 genes and 13 additional loci have been identified in ADCAs. Despite phenotypic differences, spinocerebellar ataxia 4 (SCA4) and Japanese 16q-linked ADCA type III map to the same region of 16q22.1. We report four Japanese families with pure cerebellar ataxia and a disease locus at 16q22.1. Our families yielded a peak lod score of 6.01 at marker D16S3141. To refine the candidate region, we carried out genetic linkage studies in four pedigrees with a high density set of DNA markers from chromosome 16q22.1. Our linkage data suggest that the disease locus for 16q- ADCA type III is within the 1.25-Mb interval delineated by markers 17msm and CTTT01. We screened for mu- tations in 36 genes within the critical region. Our critical region lies within the linkage interval reported for SCA4 and for Japanese 16q-ADCA type III. These data suggest that the ADCA that we have characterized is allelic with SCA4 and Japanese 16q-linked ADCA type III. Keywords Chromosome 16 · Positional cloning · 16q-ADCCA · Spinocerebellar ataxia 4 · Japan Introduction Autosomal dominant cerebellar ataxias (ADCAs) are clinically and genetically heterogeneous. ADCAs are classified into three subgroups according to their clinical features [1]. ADCA type I is characterized by ophthal- moplegia, optic atrophy, dementia, and extrapyramidal features. ADCA type II is characterized by retinopathy and extrapyramidal features. ADCA type III is charac- terized by isolated late-onset cerebellar ataxia. To date, 11 genes and 13 additional loci have been associated with ADCAs. The causative mutations in 9 of these 11 genes are expansions of a repetitive element. Expansions of polyglutamine tracts account for spino- cerebellar ataxia 1 (SCA1) [2], SCA2 [3,4], SCA3 [5], SCA6 [6], SCA7 [7], and SCA17 [8]. Expansion of a CTG repeat within a non-coding RNA is responsible for SCA8 [9], expansion of the pentanucleotide ATTCT re- peat within intron 9 of the SCA10 gene causes SCA10 [10], and a CAG repeat expansion within the promoter of PPP2R2B causes SCA12 [11]. Recently, missense muta- tions of PKCg have been identified as a cause of SCA14 [12], and a mutation of FGF14 has been reported as a cause of SCA [13]. In addition to these identified disease genes, disease loci have been mapped for SCA4 [14], SCA5 [15], SCA11 [16], SCA13 [17], SCA15 [18], SCA16 [19], SCA18 [20], SCA19 [21], SCA20 [22], SCA21 [23], SCA22 [24], SCA24 [25], and SCA25 [26], although the responsible gene has not been identified yet. SCA4 is an ADCA type I and is characterized by cerebellar ataxia with sensory axonal neuropathy. The SCA4 disease locus was originally mapped to 16q22.1 in a Utah family [14] and has subsequently been confirmed in SCA4 families from Germany [27]. Interestingly, the Japanese ADCA families that have been mapped to 16q22.1 (16q-ADCA type III) belong to R. Hirano · H. Takashima ( ) ) · R. Okubo · K. Tajima · Y. Okamoto · T. Arisato · H. Arata · M. Osame · K. Arimura Department of Neurology and Geriatrics, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan e-mail: thiroshi@m3.kufm.kagoshima-u.ac.jp Tel.: +81-99-2755332 Fax: +81-99-2657164 S. Ishida First Department of Internal Medicine, Osaka Medical College, Daigaku-cho 2-7, Takatsuki, 569-8686 Osaka, Japan K. Tsuruta Department of Neurology, Koga General Hospital, Ikeuchi-cho, 1749-11 Sudaki Miyazaki, Japan M. Nakagawa Department of Neurology and Gerontology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamikyo-ku, Kyoto 602, Japan