Biomedical subjects
Ikuko Kondo
Publications and source records attributed to Ikuko Kondo.
A novel alternative splice variant of nicastrin and its implication in Alzheimer disease.
Nicastrin interacts with gamma-secretase complex components predominantly via the N-terminal third of the transmembrane domain. The authentic transmembrane domain is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. In this study, we have identified a novel alternatively spliced transcript of nicastrin in human brain tissue. This transcript (NCSTN-DeltaE16) lacks exon 16 of nicastrin mRNA, which leads to deletion of 71 amino acids just upstream of its transmembrane domain. Its expression pattern was analyzed in the hippocampus of patients with pathologically diagnosed Alzheimer disease (cases) and non-Alzheimer dementia (controls). In patients with the APOE-epsilon4 allele, the frequency of Alzheimer disease appeared to be increased in the NCSTN-DeltaE16-positive group, but the association was not statistically significant. In conclusion, the expression of NCSTN-DeltaE16 transcript may confer some additional risk for developing Alzheimer disease beyond the risk due to ApoE-epsilon4 allele. Further investigation in larger scale population would be necessary to address its potential implication in Alzheimer disease.
Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease.
Lymphocyte-specific protein tyrosine kinase (LCK) is a lymphoid-specific, Src family protein tyrosine kinase that is known to play a pivotal role in T-cell activation and interact with the T-cell coreceptors, CD4 and CD8. It has been shown to be significantly down-regulated in Alzheimer disease (AD) hippocampus compared with non-demented controls. Furthermore, it is located in a previously identified genetic linkage region (1p34-36) associated with AD. Therefore, we consider it to be a candidate gene for AD. We examined the relationship between AD and the LCK and apolipoprotein E (APOE) genes in 376 AD (including 323 late-onset AD (LOAD) cases and 53 early-onset AD (EOAD) cases) and 378 non-demented controls using a single nucleotide polymorphism (SNP). The polymorphism in intron 1 (+6424 A/G) was significantly associated with AD risk. The odds ratio (OR) for total AD associated with the GG genotype was 1.41 (95% CI=1.06-1.87) and that for LOAD was 1.37 (95%CI=1.02-1.85), while that for APOE-epsilon4 was 5.06 (95% CI=3.60-7.12). In the APOE-epsilon4 non-carrier subgroup, the GG genotype also showed significant association (OR=1.66; 95% CI=1.16-2.38). These results indicate that the LCK is a novel risk gene for AD regardless of the APOE genotype.
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.
Identification of hippocampus-related candidate genes for Alzheimer's disease.
Alzheimer's disease (AD) is a complex multifactorial disease in which many genetic and environmental factors are involved. We performed an association study using 376 AD patients and 376 control subjects. We studied 35 single nucleotide polymorphisms in 35 genes that were significantly downregulated or upregulated only in the AD hippocampus compared with control and found that 9 single nucleotide polymorphisms were associated with AD. Our data indicated that single nucleotide polymorphisms could highly reflect differences in gene expression. Furthermore, an intronic polymorphism (+9943T/C) in POU2F1 was most significantly associated with AD (p = 0.0007). Our results suggest that POU2F1 is a candidate gene for AD.
Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms.
A total of 45 different mutations of methyl-CpG-binding protein 2 gene (MECP2) were identified in 145 of 219 Japanese patients with typical or atypical Rett syndrome (RTT) (66.2%). A missense mutation, T158M was the most common mutation of MECP2, identified in 22 (19.1%) patients, followed by four nonsense mutations, R168X (14.8%), R270X (13.0%), R255X (9.6%), and R294X (6.1%) in 115 patients with classical RTT. Two missense mutations, R133C (33.3%) and R306C (23.3%), and a nonsense mutation, R294X (13.3%), were common in 30 patients with atypical RTT, including the preserved speech variant (PSV). Frameshift mutations due to nucleotide deletion or insertion were identified in 22 patients with MECP2 mutations, and one of them had a 3.6 kb deletion encompassing exons 3 and 4. Three patients with classical RTT had a splicing anomaly. The wide spectrum of phenotypic variability in patients with RTT has been considered to be correlated with the mutation type and location in MECP2, and X-inactivation. However, most patients showed a random X-inactivation pattern evaluated by an androgen receptor gene polymorphism in this study, suggesting that a skewed X-inactivation might not be a main modification factor on clinical phenotypes of RTT. In addition, three new missense mutations, P176R, A378V and T479M, were identified in patients with RTT, but also in healthy Japanese, indicating that these mutations are non-pathogenic in Japanese. Information about rare polymorphic variations is very important for the molecular diagnosis of RTT, although rare polymorphic variants might differ among ethnic groups.
Classic Rett syndrome in a boy with R133C mutation of MECP2.
About 80% of female patients with Rett syndrome (RTT) display a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, but most males with MECP2 mutation experience severe fatal encephalopathy or non-specific X-linked mental retardation (XLMR). The existence of male RTT has been extensively discussed. We report herein a boy with classic RTT in a family with a missense mutation in MECP2. The mother exhibited slight mental retardation and was a carrier for R133C. The patient could stand with support at 12-months-old, and stereotypic hand movements appeared at 3-years-old. He became bed-ridden by 8-years-old. The R133C mutation was present in MECP2 without somatic mosaicism. A sister with R133C displayed classic RTT. The R133C mutation has been detected in female patients with classic and preserved speech variant RTT, but not in males with non-specific XLMR. These results suggest that clinical phenotypes caused by DNA mutation in MECP2 are determined by position of the mutation in the gene, and R133 represents a critical amino acid residue in the induction of RTT symptoms in humans.
Delayed reflection pressure wave: new aspects for postprandial hypotension.
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Orthostatic systolic hypotension and the reflection pressure wave.
Orthostatic hypotension (OH) is a potent predictor of cardiovascular frailty. Although OH is determined by changes in brachial blood pressure (BP), it has been reported that there are significant differences between central BP and peripheral BP. The prevalence of OH has been reported to be higher in subjects with isolated systolic hypertension. Since an early returning of the reflection pressure wave due to advanced arterial stiffness is one of the underlying mechanisms of systolic hypertension, a significant association between alterations of the reflection pressure wave and OH has been hypothesized. To explore this hypothesis, the orthostatic changes in carotid BP and arterial waveform were evaluated. The study subjects were 155 community residents (69 +/- 7 years old). Carotid and brachial BP were measured simultaneously in the supine position and 1 min after standing using a cuff-oscillometric and tonometric method. The carotid augmentation index (AIx) was obtained from the pressure waveform. The orthostatic decline of BP was more prominent in the carotid artery than the brachial artery. Nine subjects were diagnosed with orthostatic systolic hypotension (OSH) from brachial BP, while 21 subjects were diagnosed from carotid BP (p < 0.001). The orthostatic change in carotid systolic BP was significantly associated with that in carotid AIx (r = 0.361, p < 0.001). The decline of the reflection component of carotid pulse pressure (-4.0 +/- 8.4 mmHg) was more prominent than that of the incident component (-1.2 +/- 9.9 mmHg, p = 0.002). These results indicate that evaluation of brachial BP may not represent the orthostatic changes in central BP. Alteration of the reflection pressure wave could be one of the underlying mechanisms of OSH in the central artery.
Hypotension associated with prone body position: a possible overlooked postural hypotension.
Conditions related to the dysregulation of blood pressure (BP), such as orthostatic hypotension, have been shown to be significantly associated with cardiovascular disease. Recently, the prone body position has been recognized as a possible postural factor leading to BP dysregulation. We conducted a cross-sectional study to investigate the BP response to a change in body position from supine to prone. The study subjects consisted of 271 middle-aged healthy males, randomly selected from the employees of a large manufacturing enterprise in Ehime Prefecture, Japan. Brachial BP and heart rate were measured in a sitting, supine and prone position, in that order, and each difference was defined as a postural change. The postural changes in aortic hemodynamics were also assessed using a SphygmoCor system. The basal BP measured in the sitting position was significantly decreased in the supine position (132+/-18 to 130+/-17 mmHg, p<0.001). A further reduction was observed after the postural change from supine to prone (130+/-17 to 125+/-16 mmHg, p<0.001). The heart rate was increased with the supine-to-prone postural change (4.1+/-5.8 beats/min, p<0.001), while it showed a significant decrease with the sitting-to-supine postural change (-7.6+/-5.6 beats/ min, p<0.05). The impact of BP reduction was more prominent in the aortic artery (-3.3+/-6.7%) than the brachial artery (-3.0+/-6.3%, p=0.020). Multiple regression analysis showed that basal systolic BP was a solely significant determinant of the prone-hypotension (beta=-0.309, p<0.001). In conclusion, these results indicate that lying in a prone posture could lead to unregulated postural hypotension, which has the possibility of being a novel predictor of cardiovascular frailty.
Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease.
Fibroblast growth factor 1 (FGF1, also known as acidic FGF) protects selective neuronal populations against neurotoxic effects such as those in Alzheimer's disease (AD) and HIV encephalitis. The FGF1 gene is therefore a strong candidate gene for AD. Using the promoter polymorphism of the FGF1 gene, we examined the relationship between AD and the FGF1 and apolipoprotein E (APOE) genes in 100 Japanese autopsy-confirmed late-onset AD patients and 106 age-matched non-demented controls. The promoter polymorphism (-1385 A/G) was significantly associated with AD risk. The odds ratio for AD associated with the GG vs non-GG genotype was 2.02 (95% CI = 1.16-3.52), while that of s4 vs non-ł4 in APOE4 gene was 5.19 (95% CI = 2.68-10.1). The odds ratio for APOEP4 and FGF1 GG carriers was 20.5 (95% CI = 6.88-60.9). The results showed that the FGF1 gene is associated with autopsy-confirmed AD.
TAFI polymorphisms at amino acids 147 and 325 are not risk factors for cerebral infarction.
Thrombin-activatable fibrinolysis inhibitor (TAFI) was reported as an anaphylatoxin-inactivating enzyme generated by proteolytic cleavage of its zymogen, and is the same enzyme as that first designated by our group as procarboxypeptidase R (proCPR). Its level in plasma appears to influence vascular disease. In addition, TAFI activity is strongly influenced by genetic polymorphism, especially at amino acids 147 and 325. We investigated whether these TAFI polymorphisms would act as a risk factor for cerebral infarction (CI) by examining 253 samples in which the diagnosis was cliniconeuropathologically confirmed. We found little that was statistically significant in terms of these polymorphisms among patients with no vascular problems or in a population-based control group. In the present study of an elderly Japanese group, our samples revealed a lower percentage of the Ile allele at Thr/Ile-325 compared with western counterparts. Although patients with severe infarcts had a lower percentage of the Ile allele (10%) at amino acid position 325 compared with the slightly and moderately affected patients and the population-based control group (15-18%), no statistical significance was found. None of our results showed any statistical correlation between TAFI polymorphisms and CI.
Home blood pressure is a better predictor of carotid atherosclerosis than office blood pressure in community-dwelling subjects.
An increase in the thickness of the intima-media (IMT) of the carotid artery is associated with an increased risk of cardiovascular morbidity and mortality. Hypertension is one of the underlying mechanisms for the progression of carotid atherosclerosis. However, office blood pressure (BP) has been shown to have only a weak association with carotid IMT. Since self-measured home BP has less variation than office BP, home BP could be a better predictor of carotid atherosclerosis. To explore this hypothesis, we compared the relationships between carotid IMT and office BP or home BP in a community-dwelling population. One-hundred and one community residents, aged 50 years or older and not taking any medication, were enrolled in this study. Morning home BP was measured according to the guidelines of the Japanese Society of Hypertension. The results were recorded for 2 weeks and averaged. Carotid atherosclerosis was defined as IMT > or =0.80 mm, which corresponds to the first quartile. Home systolic BP showed a more significant association with carotid IMT (r=0.422, p <0.0001) than with office systolic BP (r=0.021, p=0.027). Logistic regression analysis for the presence of carotid atherosclerosis further showed that the relative risk of hypertension defined using home BP (> or =135/85 mmHg) was 6.3 (95% confidence interval [CI]: 2.0 to 19.6), while that using office BP was 1.5 (95% CI: 0.5 to 4.2). These results suggest that home BP is a better predictor of the development of carotid atherosclerosis than office BP.
Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors.
The effect of genetic polymorphism of human organic anion transporting polypeptide C (OATP-C) on the lipid-lowering response to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors was assessed. A retrospective study was conducted on 66 patients who underwent treatment of hyperlipidemia with HMG-CoA reductase inhibitors in a municipal hospital in a community-based cohort of Ehime prefecture in the southern part of Japan. Plasma lipid concentrations before and after administration were analyzed in patients in relation to the 521T/C (Val-174-->Ala) polymorphism in the OATP-C gene (TT: n=44 (66.7%), TC: n=20 (30.3%), CC: n=0 (0.0%), undetermined: n=2 (3.0%)). Total cholesterol level was significantly lowered after treatment with HMG-CoA reductase inhibitors in all patients (p<0.001); moreover, subjects with the 521C allele showed an attenuated total-cholesterol-lowering effect compared with those homozygous for the 521T allele (-22.3+/-8.7% vs. -16.5+/-10.5%, p<0.05). These data suggest that the 521T/C polymorphism of the OATP-C gene modulates the lipid-lowering efficacy of HMG-CoA reductase inhibitors.
A novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains: a candidate gene for benign adult familial myoclonic epilepsy on human chromosome 8q23.3-q24.1.
We identified a novel giant gene encoding a transmembrane protein with CUB and sushi multiple domains on the human chromosome 8q23.3-q24.1 in which benign adult familial myoclonic epilepsy type 1 (BAFME1/FAME, OMIM:601068) has been mapped. This giant gene consists of 73 exons and spans over 1.2Mb on the genomic DNA region. It showed significant homology to two genes, CSMD1 gene on 8p23 and CSMD2 gene on 1p34, at reduced amino acid sequence level and hence we designated as CSMD3. The CSMD3 gene was expressed mainly in adult and fetal brains. We performed mutation analysis on the CSMD3 gene for seven patients with BAFME1/FAME, but no mutation was found in the coding sequence of the CSMD3 gene. Comparative genomic analysis revealed a conserved family of CSMD genes in the mouse and fugu genomes. Possible functions of the CSMD gene family are discussed.
Polymorphism of the monocyte chemoattractant protein (MCP-1) gene is associated with the plasma level of MCP-1 but not with carotid intima-media thickness.
Monocyte chemoattractant protein-1 (MCP-1) plays an important role in atherosclerosis. Recently, single nucleotide polymorphisms (SNPs) in the MCP-1 regulatory region have been identified, and an in vitro study demonstrated that the SNP at position -2518 of the MCP-1 gene affected transcription of the gene. The purpose of this study was to clarify the association of the plasma level of MCP-1 and the SNP of the MCP-1 gene with carotid atherosclerosis in community-based subjects. The study subjects consisted of 325 community residents, aged 50 years or older (mean age, 70.5 +/- 9.4 years) and free from any cardiovascular complications. Carotid intima-media thickness (IMT) was measured in the right common carotid artery using ultrasonography. The plasma level of MCP-1 was measured by enzyme-linked immunosorbent assay (ELISA). The SNP of the MCP-1 gene was determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique. The plasma level of MCP-1 was significantly associated with IMT (r = 0.12, p < 0.05) and carotid arterial dimension (r = 0.13, p < 0.05). There was a significant difference in plasma MCP-1 level between the genotypes (AA, 166 +/- 36 ng/ml; GG + AG, 184 +/- 56 ng/ml; p = 0.036). Analysis restricted to the subjects not receiving antihypertensive drugs or other medication further increased the statistical significance. However, carotid IMT and carotid arterial diameter were not significantly different among the MCP-1 genotypes. Stepwise regression analysis for plasma MCP-1 revealed that the MCP-1 genotype was an independent determinant of plasma MCP-1 level. These findings indicate that plasma MCP-1 is associated with carotid atherosclerosis. Although -2518 SNP is associated with the plasma level of MCP-1, it was not directly associated with carotid atherosclerosis.
Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans.
Male embryonic mice with mutations in the X-linked aristaless-related homeobox gene (Arx) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia (XLAG) in humans. We found multiple loss-of-function mutations in ARX in individuals affected with XLAG and in some female relatives, and conclude that mutation of ARX causes XLAG. The present report is, to our knowledge, the first to use phenotypic analysis of a knockout mouse to identify a gene associated with an X-linked human brain malformation.
Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: Identification of two novel mutations and establishment of multiple DNA diagnosis methods for nine mutations.
We have recently identified SLC25A13 on chromosome 7q21.3 as the gene responsible for adult-onset type II citrullinemia (CTLN2) and found seven mutations in the SLC25A13 gene of CTLN2 patients. Most recently, the SLC25A13 mutations have been detected in neonatal/infantile patients with a type of neonatal hepatitis associated with cholestasis (NICCD). In the present study, we identified a novel mutation, E601X, in the SLC25A13 gene and established multiple DNA diagnosis methods for eight mutations by using a genetic analyzer with GeneScan and the single primer extension procedure (SNaPshot). An additional novel missense mutation (variation), E601K, was detected by SNaPshot analysis and was indistinguishable from the mutation E601X detected by the PCR/RFLP method. Multiple DNA diagnoses for the nine mutations revealed that 100 (male/female: 70/30) out of 115 CTLN2 and 38 (14/24) out of 45 NICCD patients tested were homozygotes or compound heterozygotes. The frequency of homozygotes carrying SLC25A13 mutations in both alleles is estimated to be minimally 1 in 21,000 from carrier detection (18 in 1,315 individuals tested) in the Japanese population. The differences in the gender ratio and in mutation types between CTLN2 and NICCD patients are significant. It is, however, unknown whether all homozygotes with mutated SLC25A13 in both alleles suffer from NICCD, CTLN2, both, or neither.