Japanese Familial Amyotrophic Lateral Sclerosis Research Articles

Targeted next-generation sequencing in japanese familial amyotrophic lateral sclerosis reveals diffrences in the genetic variations across populations

Targeted next-generation sequencing in japanese familial amyotrophic lateral sclerosis reveals diffrences in the genetic variations across populations

Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients. A novel likely pathogenic homozygous variant in ALS2 was identified in 1 patient. In addition, 18 patients harbored 1–3 novel variants of uncertain significance, whereas hexanucleotide repeat expansions in C9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG, and OPTN variants were 32%, 11%, 2%, 2%, 1%, and 1%, respectively. These findings indicate considerable differences in the genetic variations associated with familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted.

Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis

TAR-DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene on chromosome 1p36.22, has been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS), SOD1-negative familial ALS (FALS) and frontotemporal lobar dementia (FTLD). Twenty mutations of TARDBP in SOD1-negative FALS and SALS cases have been reported so far. To investigate the presence and frequency of TARDBP mutations in Japanese SOD1-negative FALS patients, we performed mutational screening of TARDBP in 30 SOD1-negative FALS patients. An N352S mutation was found in one case of FALS, but no TARDBP mutations were found in cases of SALS. It was thought that this mutation increases TDP-43 phosphorylation. This might lead to impaired nuclear cytoplasmic transport or protein–protein interaction, thereby leading to TDP-43 accumulation.

Japanese familial amyotrophic lateral sclerosis family with a two‐base deletion in the superoxide dismutase‐1 gene

The clinical characteristics of members of a familial amyotrophic lateral sclerosis (FALS) family from Oki Island, whose members have a 2‐bp deletion at codon 126 of Cu/Zn superoxide dismutase (SOD1) gene, are presented here. Mean age of the onset in the members was 42 years. Mean disease duration among the members who had not been placed on a respirator was approximately 2 years. Long‐term survivors with respiratory support presented disturbances in eye movement and urination toward the end stages of the disease. They predominantly exhibited lower motor neuron symptoms. In addition, the authors focused on frameshift, nonsense and non‐amino‐acid‐altering mutations. Frameshift and nonsense mutations were all found within exon 4, exon 5 and intron 4. These amyotrophic lateral sclerosis cases were likely to have shorter disease duration than the FALS patients with single substitution. Several hypotheses were presented on the pathogenesis of FALS with SOD1 mutation.

Japanese familial amyotrophic lateral sclerosis family with a two-base deletion in the superoxide dismutase-1 gene.

The clinical characteristics of members of a familial amyotrophic lateral sclerosis (FALS) family from Oki Island, whose members have a 2-bp deletion at codon 126 of Cu/Zn superoxide dismutase (SOD1) gene, are presented here. Mean age of the onset in the members was 42 years. Mean disease duration among the members who had not been placed on a respirator was approximately 2 years. Long-term survivors with respiratory support presented disturbances in eye movement and urination toward the end stages of the disease. They predominantly exhibited lower motor neuron symptoms. In addition, the authors focused on frameshift, nonsense and non-amino-acid-altering mutations. Frameshift and nonsense mutations were all found within exon 4, exon 5 and intron 4. These amyotrophic lateral sclerosis cases were likely to have shorter disease duration than the FALS patients with single substitution. Several hypotheses were presented on the pathogenesis of FALS with SOD1 mutation.

A novel mutation Asp90Val in the SOD1 gene associated with Japanese familial ALS

We have identified a novel mutation in exon 4 of the Cu/Zn superoxide dismutase (superoxide dismutase 1: SOD1) gene (GAC to GTC), which resulted in an Asp90 to Val substitution in a Japanese family with amyotrophic lateral sclerosis (ALS) inherited as an autosomal dominant trait. The patients in this family usually died in 2–3 years without sensory or urinary impairment. The SOD1 activity was lower in the proband as compared to the normal controls. The clinical characteristics of this family resemble those of some patients heterozygous for the Asp90Ala mutation, but both the clinical features and SOD1 activity of this family differ from those of patients homozygous for the ASP90Ala mutation.

Abnormality of Cu/Zn superoxide dismutase (SOD1) activity in Japanese familial amyotrophic lateral sclerosis with two base pair deletion in the SOD1 gene.

Abnormality of Cu/Zn superoxide dismutase (SOD1) activity in Japanese familial amyotrophic lateral sclerosis with two base pair deletion in the SOD1 gene.

Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in [formula omitted] superoxide dismutase gene: A possible new subtype of familial ALS

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder that results in relentless damage to the motor neuron system. Although about 5–10% of cases are familial, the pathophysiologic process of ALS remains unknown. We identified a novel point mutation A to G in exon 2 of the Cu Zn SOD gene, resulting in an amino acid substitution of histidine 46 by arginine (H46R), in two Japanese familial ALS (FALS) families. The segregations of the mutation were evident. The enzymatic activities of Cu Zn SOD of peripheral red blood cell lysate were reduced to about 80% in the affected members, compared with other non-affected family members. The patients in these families are clinically characterized by relative late onset, initial involvement in lower extremities, relative rare impairment of bulbar muscles and much slow progression of muscular weakness and atrophy, compared with other Japanese FALS cases who have no mutation in the Cu Zn SOD gene. These findings suggest that the H46R mutation in Cu Zn SOD gene is highly related to this unique subtype of FALS.

A Novel Mutation in Cu/Zn Superoxide Dismutase Gene in Japanese Familial Amyotrophic Lateral Sclerosis

Recently, several missense mutations in the Cu/Zn superoxide dismutase gene ( SOD1) have been reported as a putative cause of chromosome-21q-linked familial amyotrophic lateral sclerosis (FALS). We have discovered a novel missense mutation (substitution of Thr for Ala 4) in exon 1 ( G CC to A CC) in two FALS patients from one Japanese FALS family. No mutations were found in 17 cases of sporadic ALS. The enzyme activity of recombinant fusion protein containing the Cu/Zn superoxide dismutase (SOD) with the Ala 4-to-Thr mutation was significantly reduced in E. coli. On the other hand, in the expression system in insect cells using Baculovirus, the mutant SOD expressed an enzyme activity as high as wild-type SOD. These results suggest that the stability of SOD with the Ala 4-to-Thr mutation is disrupted especially in the fusion protein. Autopsy was carried out on one of the two patients, and the pathological findings were typical of FALS with posterior column involvement. These results raise the possibility that mutation of the SOD1 is responsible for FALS with broader pathological involvement.