Integrative Annotation of 21,037 Human Genes Validated by Full-Length cDNA Clones

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology

知能正常で頭部CT上白質の瀰漫性低吸収域を示す先天性筋ジストロフィーの日本人小児例 : 16年間経過を追った症例について

先天性筋ジストロフィー(CMD)という語は,生下時または生後数ヵ月以内に筋力低下を示し,筋生検ではジストロフィー変化を示す乳児に対し広く用いられてきた.本邦では知能障害を伴う福山型CMDが知られ症例も多い.欧米例は,一般に知能障害は伴わず,筋症状だけを示すと考えられてきた.Nogenが知能は正常であるがCT上白質の瀰漫性の低吸収域を呈するCMD例を報告し,続いて同様の症例が報告され,知能障害は伴わないが中枢神経系に異常のあるCMDの存在が注目を浴びるようになった.1994年にこれらと臨床像が一致する例でメロシンの欠損が認められ,遺伝子座は6q2に存在することが判明した.我々は,生下時より著明な筋力低下を呈し,知能正常,瀰漫性白質低吸収域を呈するCMD例を経験し1981年CMDII型として報告した.さらに,知能正常,生後まもなく筋力低下を示し,筋生検ではジストロフィー変化を呈する同様な例を3例経験した.いずれも生後3ヵ月以前に発症し,定頚が7ヵ月以降と遅れていた.しかしながら,1例を除き坐位保持は1歳未満で獲得しており,いざり這いも可能となった.仮性肥大を認めず,顔筋罹患は軽度に止まり,年長時には顔が細長く見える.1例は, 22歳まで経過観察したが,4歳時および19歳時の頭部CTではいずれも瀰漫性白質低吸収域を認め,両所見に差は認めなかった.最高運動機能はいざり這いで,2歳6ヵ月より11歳まで可能であった.同様の本邦報告例は散見されるが,16年間という長期経過を観察可能であった例は他になく,本邦および欧米例の文献展望を加え,本症の位置付け,分類上の今後の問題点などを検討報告した.A 22y7m old male with non-Fukuyama type congenital muscular dystrophy (non-FCMD), suffering from profound muscle weakness, pes equinovarus since early infancy, with entirely normal mentality despite diffuse white matter hyperlucency on computed tomography without ventricular dilatation, who had been examined at four and 20 years of age with essentially no change during the 16 year interval, is reported. Congenital muscular dystrophy was diagnosed at 8m based on an elevated serum creatine kinase (CK) value and the results of electromyography and muscle biopsy. He never became ambulant but did attain head control, the ability to maintain a sitting posture and sliding on his buttocks. Maximum motor ability was maintained until age 11y. Involvement of the facial musculature and multiple joint contractures developed. He experienced convulsions induced by a fever. Leukocyte lysosomal enzymes were all within normal limits. Cerebrospinal fluid was negative for demyelinating antibodies. Motor nerve conduction velocities examined at 4y2m were within normal limits. Genetic analysis of the FCMD gene locus revealed the patient to have the same haplotype, in terms of the centromere side of mfd220, as one of his healthy elder brothers with normal CK values. In addition, we have reviewed the literature on non-FCMD with similar findings and present two other similar cases in our experience

知能正常で頭部CT上白質の瀰漫性低吸収域を示す先天性筋ジストロフィーの日本人小児例 : 16年間経過を追った症例について

先天性筋ジストロフィー(CMD)という語は,生下時または生後数ヵ月以内に筋力低下を示し,筋生検ではジストロフィー変化を示す乳児に対し広く用いられてきた.本邦では知能障害を伴う福山型CMDが知られ症例も多い.欧米例は,一般に知能障害は伴わず,筋症状だけを示すと考えられてきた.Nogenが知能は正常であるがCT上白質の瀰漫性の低吸収域を呈するCMD例を報告し,続いて同様の症例が報告され,知能障害は伴わないが中枢神経系に異常のあるCMDの存在が注目を浴びるようになった.1994年にこれらと臨床像が一致する例でメロシンの欠損が認められ,遺伝子座は6q2に存在することが判明した.我々は,生下時より著明な筋力低下を呈し,知能正常,瀰漫性白質低吸収域を呈するCMD例を経験し1981年CMDII型として報告した.さらに,知能正常,生後まもなく筋力低下を示し,筋生検ではジストロフィー変化を呈する同様な例を3例経験した.いずれも生後3ヵ月以前に発症し,定頚が7ヵ月以降と遅れていた.しかしながら,1例を除き坐位保持は1歳未満で獲得しており,いざり這いも可能となった.仮性肥大を認めず,顔筋罹患は軽度に止まり,年長時には顔が細長く見える.1例は, 22歳まで経過観察したが,4歳時および19歳時の頭部CTではいずれも瀰漫性白質低吸収域を認め,両所見に差は認めなかった.最高運動機能はいざり這いで,2歳6ヵ月より11歳まで可能であった.同様の本邦報告例は散見されるが,16年間という長期経過を観察可能であった例は他になく,本邦および欧米例の文献展望を加え,本症の位置付け,分類上の今後の問題点などを検討報告した.A 22y7m old male with non-Fukuyama type congenital muscular dystrophy (non-FCMD), suffering from profound muscle weakness, pes equinovarus since early infancy, with entirely normal mentality despite diffuse white matter hyperlucency on computed tomography without ventricular dilatation, who had been examined at four and 20 years of age with essentially no change during the 16 year interval, is reported. Congenital muscular dystrophy was diagnosed at 8m based on an elevated serum creatine kinase (CK) value and the results of electromyography and muscle biopsy. He never became ambulant but did attain head control, the ability to maintain a sitting posture and sliding on his buttocks. Maximum motor ability was maintained until age 11y. Involvement of the facial musculature and multiple joint contractures developed. He experienced convulsions induced by a fever. Leukocyte lysosomal enzymes were all within normal limits. Cerebrospinal fluid was negative for demyelinating antibodies. Motor nerve conduction velocities examined at 4y2m were within normal limits. Genetic analysis of the FCMD gene locus revealed the patient to have the same haplotype, in terms of the centromere side of mfd220, as one of his healthy elder brothers with normal CK values. In addition, we have reviewed the literature on non-FCMD with similar findings and present two other similar cases in our experience

A novel cyclic peptide (Naturido) modulates glia-neuron interactions in vitro and reverses ageing-related deficits in senescence-accelerated mice.

The use of agents that target both glia and neurons may represent a new strategy for the treatment of ageing disorders. Here, we confirmed the presence of the novel cyclic peptide Naturido that originates from a medicinal fungus (Isaria japonica) grown on domestic silkworm (Bombyx mori). We found that Naturido significantly enhanced astrocyte proliferation and activated the single copy gene encoding the neuropeptide VGF and the neuron-derived NGF gene. The addition of the peptide to the culture medium of primary hippocampal neurons increased dendrite length, dendrite number and axon length. Furthermore, the addition of the peptide to primary microglial cultures shifted CGA-activated microglia towards anti-inflammatory and neuroprotective phenotypes. These findings of in vitro glia-neuron interactions led us to evaluate the effects of oral administration of the peptide on brain function and hair ageing in senescence-accelerated mice (SAMP8). In vivo analyses revealed that spatial learning ability and hair quality were improved in Naturido-treated mice compared with untreated mice, to the same level observed in the normal ageing control (SAMR1). These data suggest that Naturido may be a promising glia-neuron modulator for the treatment of not only senescence, but also Alzheimer's disease and other neurodegenerative diseases