Novel deletion mutations of OPTN in amyotrophic lateral sclerosis in Japanese.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron death in the brain and spinal cord. Many disease genes for ALS have been identified; however, each disease gene is responsible for very small fractions of ALS. Recently, mutations of the gene encoding optineurin (OPTN) are reported in familial and sporadic ALS. OPTN is also responsible for a small number of ALS, 3.8% of familial and 0.29% of sporadic ALS in Japanese. The low prevalence may be an underestimation due to incomplete screening of the mutation. To examine OPTN mutations more extensively, we screened the OPTN deletions using a quantitative PCR system. We examined 710 Japanese ALS subjects who had previously been found to have no OPTN mutations by a screening using a PCR-direct sequence strategy. We identified 3 kinds of deletions in 5 patients; one was homozygous, and the remaining were heterozygous. All deletions occurred due to the Alu-mediated recombination and are expected to result in null alleles. Our results suggest that the OPTN deletion mutation in ALS is not infrequent and the prevalence of the OPTN mutation in Japanese sporadic ALS is considerably high.

Large-scale screening of TARDBP mutation in amyotrophic lateral sclerosis in Japanese.

Mutations in TARDBP encoding TDP (TAR DNA binding protein)-43 have been reported in familial and sporadic amyotrophic lateral sclerosis (ALS), but mostly in Caucasians. In other ethnic groups, four types of mutations are found in familial ALS. In sporadic ALS, the TARDBP mutations frequency is low in Caucasians (0-5%) and no mutation has been found in other ethnic groups. To examine spectrum of TARDBP mutations and its frequency in Japanese, we screened the TARDBP mutation in 721 Japanese ALS by direct sequencing. We identified a novel mutation, c.1069G > A (p.Gly357Ser) and a known mutation in sporadic ALS. One patient was homozygous for p.Gly357Ser, which was the first for TARDBP mutation. Our study showed that TARDBP mutations also occur in non-Caucasian sporadic ALS. The estimated frequency of the TARDBP mutation in sporadic ALS is 0.29% in Japanese. The mutation frequency in familial ALS in Japanese is also similar to that in Caucasian, and is ∼10 times higher than that in Japanese sporadic ALS.

A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P= 9.3 × 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-ß (TGF-ß) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls.  Our results strongly suggest that ZNF512B is an important positive regulator of TGF-ß signaling and that decreased ZNF512B expression increases susceptibility to ALS.

Replication analysis of SNPs on 9p21.2 and 19p13.3 with amyotrophic lateral sclerosis in East Asians.

We performed a replication study of the 2 genetic variants, rs2814707 on 9p21.2 and rs12608932 on 19p13.3 that are recently reported to be most significantly associated with sporadic amyotrophic lateral sclerosis (ALS) in Caucasians. Both rs12608932 and rs2814707 showed no evidence of association in Japanese and Chinese (rs12608932, combined p = 0.58, odds ratio [OR] = 1.03, 95% confidence interval [CI] 0.93-1.13; rs2814707, combined p = 0.88, OR = 1.10, 95% CI 0.93-1.30). The association of these loci with susceptibility to sporadic ALS is considered negative in East Asians.