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Biomedical subjects

T Kohno

Publications and source records attributed to T Kohno.

At least 145 records · Page 8Linked to original sources
PubMed1999

Prognostic significance of allelic imbalances on chromosome 9p in stage I non-small cell lung carcinoma.

Loss of heterozygosity (LOH) on chromosomes 2q, 9p, 18q, and 22q frequently occurs in advanced non-small cell lung carcinoma (NSCLC). The association of p53 mutations with prognosis is still unclear in NSCLC. Therefore, we investigated the prognostic significance of allelic imbalances (AI) on these chromosomes and p53 mutations in 108 cases of stage I NSCLC by PCR amplification of polymorphic dinucleotide repeat-containing sequences and PCR-single strand conformation polymorphism analysis. AI on 2q, 9p, 18q, and 22q was detected in 22, 38, 29, and 15% of cases, respectively, whereas p53 was mutated in 41% of stage I NSCLC. AI on 9p and 22q and p53 mutations were significantly associated with shortened survival of the patients (P = 0.010, 0.024, and 0.022, respectively). Although gender and smoking history showed more significant associations with prognosis than other clinicopathological and molecular parameters, independent prognostic significance for AI on 9p was observed (P = 0.002) in male patients with a positive smoking history. These results indicate that clinical aggressiveness of early-stage NSCLC can be partly defined by the presence of AI on chromosome 9p in cancer cells, and that AI on 9p could be a clinically useful prognostic indicator for early-stage NSCLC patients.

Adult↗
PubMed1999

hOGG1 Ser326Cys polymorphism and lung cancer susceptibility.

The human homologue of the yeast OGG1 gene, hOGG1, has been cloned, and its genetic structure has been determined. Several polymorphisms in the hOGG1 gene were detected in the Japanese populations, and among them, the Ser-Cys polymorphism at codon 326 has been shown to have a functional difference in complementation of mutant Escherichia coli that is defective in the repair of 8-hydroxyguanine. Activity in the repair of 8-hydroxyguanine is greater in hOGG1-Ser326 protein than in hOGG1(326) protein. Because many environmental carcinogens produce 8-hydroxyguanine residue and mismatching to this modified base potentially causes oncogenic mutations, the capacity to repair these lesions can be involved in cancer susceptibility in human beings. We, therefore, examined allele distributions of the Ser326Cys polymorphism in a case-control study of male lung cancer in Okinawa. The analyses based on 241 cases and 197 hospital controls disclosed the following findings. (a) Those with the Cys/Cys genotype were at an increased risk of squamous cell carcinoma and nonadenocarcinoma compared to those with the Ser/Cys and those with the Ser/Ser genotypes combined. The odds ratios adjusted for age and smoking history were 3.01 (95% confidence interval, 1.33-6.83) and 2.18 (95% confidence interval, 1.05-4.54), respectively. (b) The odds ratios for other histological subtypes of lung cancer or those in total were not significant. Those for Cys/Cys or Ser/Cys genotype against Ser/Ser did not reach statistical significance in any cell type. (c) The distributions of this polymorphism varied for different populations (Chinese, Japanese, Micronesians, Melanesians, Hungarians, and Australian Caucasians), with much less prevalence of Cys allele in the latter three populations. Although our sample size was limited, these results indicate that the Ser326Cys variant may be related to squamous cell lung cancer susceptibility. The Cys/Cys genotype appears to be more susceptible to squamous cell carcinoma, although the risk is less than that previously reported to be associated with the CYP1A1 gene. Further studies are needed to assess the importance of the interpopulation variation to cancer susceptibility.

Adult↗
PubMed1998

High-resolution solution NMR structure of the minimal active domain of the human immunodeficiency virus type-2 nucleocapsid protein.

The retroviral nucleocapsid (NC) protein is a multifunctional protein essential for RNA genome packaging and viral infectivity. The NC protein, NCp8, of the human immunodeficiency virus type-II (HIV-2) is a 49 amino acid peptide containing two zinc fingers, of the type C-X2-C-X4-H-X4-C, connected by seven amino acid residues, called the "basic amino acid cluster." It has been shown that the N-terminal zinc finger flanked by the basic amino acid cluster is the minimal active domain for the specific binding to viral RNA and other functions. However, the structure-activity relationships of NCp8 have not been investigated in detail. In the present study, the three-dimensional structure of a 29 amino acid peptide, including the minimal active domain (NCp8-fl), was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 15 converged structures of NCp8-fl were obtained on the basis of 355 experimental constraints, including 343 distance constraints obtained from nuclear Overhauser effect connectivities, 12 torsion angle (phi, chi1) constraints, and four constraints for zinc binding. The root-mean-square deviation of the 15 converged structures was 0.29 +/- 0.04 A for the backbone atoms (N, C(alpha), C) and 1.27 +/- 0.13 A for all heavy atoms. Interestingly, the basic amino acid cluster itself was defined well, with a loop-like conformation in which three arginine residues in the cluster and one arginine residue in the zinc finger are located approximately in the same plane of the molecule and are exposed to the solvent. The structure-activity relationships are discussed on the basis of the comparison of this well-defined structure with those of other NC proteins.

Amino Acid Sequence↗
PubMed1998

Minimal effect of brain temperature changes on glutamate release in rat following severe global brain ischemia: a dialysis electrode study.

Using a dialysis electrode, we recently developed an oxygen-independent system for real-time measurement of the glutamate concentration in the extracellular space ([Glu]e) during ischemia. This system allows separate evaluation of intra-ischemic biphase [Glu]e elevation, i.e. release from synaptic vesicles (1st phase), reversed uptake of glutamate from metabolic pools in neuronal cells (2nd phase), and post-ischemic glutamate re-uptake in ischemia-reperfusion models. Using the system, we attempted to clarify the relationship between biphase glutamate release and brain temperature in a model of acute global ischemia produced by transecting both carotid arteries. Our results showed that, in contrast to mild hyperthermia, hypothermia did not inhibit the 1st phase of [Glu]e release, and changes in intra-ischemic brain temperature had a minimal effect on the 2nd phase of [Glu]e elevation during severe acute ischemia. These findings, together with our previous data, indicate that brain temperature change in the intra-ischemic period plays an important role in disturbance of the glutamate re-uptake system during ischemia.

Animals↗
PubMed1998

Clinicopathological significance of Fhit protein expression in stage I non-small cell lung carcinoma.

Abnormalities in structure and expression of the FHIT gene have been detected in a considerable fraction of primary lung tumors. Previous reports indicated that FHIT gene alterations can be simply detected by immunohistochemical methods. Therefore, we investigated the association of Fhit expression with clinicopathological features and allelic imbalance (AI) at the FHIT locus in 105 stage I non-small cell lung cancers (NSCLC) by the immunohistological method and PCR analysis. Thirty-six of 105 (34%) tumors showed marked reduction of Fhit immunoreactivity. Fhit expression was markedly reduced in most squamous cell carcinomas (24 of 28, 86%), whereas such a reduction was detected only in a small subset of adenocarcinomas (7 of 67, 10%; P < 0.001). A marked reduction of Fhit protein expression was observed more frequently in patients with a smoking history (32 of 80, 40%) than in patients without a smoking history (4 of 25, 16%; P = 0.013). These results indicate that FHIT gene alterations preferentially occur in squamous cell carcinomas and in smokers. Furthermore, a reduction of Fhit protein expression in tumor cells was associated with a poorer survival of patients with stage I NSCLC, irrespective of histological subtypes of tumors (P = 0.005; log-rank test). Fhit expression was reduced preferentially in tumors with AI at the FHIT locus; however, AI at the FHIT locus did not correlate with patients' survival (P = 0.262; log-rank test). These results suggested that Fhit protein expression could be a useful molecular marker for the prognosis of patients with surgically resected stage I NSCLC.

Acid Anhydride Hydrolases↗
PubMed1998

Effects of brain temperature on CBF thresholds for extracellular glutamate release and reuptake in the striatum in a rat model of graded global ischemia.

We simultaneously measured extracellular glutamate ([Glu]e) elevation and local CBF using a real-time monitoring method and laser-Doppler flowmetry, respectively, in the rat striatum in a modified graded global ischemia model. Ischemic brain temperatures were kept at 32 degrees C, 37 degrees C and 39 degrees C. Three distinct types of intraischemic [Glu]e elevation, reflecting mild, moderate and massive glutamate release, were observed. Brain temperature plays an important role in determining CBF thresholds for each of the three types of [Glu]e elevation. CBF thresholds for [Glu]e elevations shifted to a lower level range as brain temperature was reduced. In mild or moderate ischemia, there is no exposure to sustained [Glu]e elevation, which is seen only in relatively severe ischemia characterized by biphasic [Glu]e elevation.

Animals↗
PubMed1998

Identification of stathmin as a novel substrate for p38 delta.

p38 mitogen-activated protein kinases (MAPK) are a family of kinases that are activated by cellular stresses and inflammatory cytokines. Although there are many similarities shared by the isoforms of p38 (alpha, beta, gamma, and delta), p38 delta differs from the others in some respects such as inhibitor sensitivity and substrate specificity. Utilizing in a solution kinase assay, we identified a novel p38 delta substrate as stathmin. Stathmin is a cytoplasmic protein that was previously reported to be a substrate of several intracellular signaling kinases and has recently been linked to regulation of microtubule dynamics. p38 delta has significantly higher in vitro phosphorylating activity against stathmin than other p38 isoforms or related MAPKs. In transient expression studies, we found that in addition to different stimuli osmotic stress activates p38 delta to phosphorylate stathmin. The sites of phosphorylation were mapped to Ser-25 and Ser-38, both in vitro and in cells.

Base Sequence↗
PubMed1998

A novel tumor suppressor locus on chromosome 18q involved in the development of human lung cancer.

The high incidence of loss of heterozygosity (LOH) on chromosome 18q in advanced non-small cell lung carcinomas indicates the presence of tumor suppressor gene(s) on this chromosome arm, which plays an important role in the acquisition of malignant phenotypes in lung cancers. In the present study, we examined 62 lung cancer specimens and 54 lung cancer cell lines for allelic imbalance at 11 microsatellite loci to define common regions of 18q deletions. Allelic imbalance of 18q was detected in 24 (55.8%) non-small cell lung carcinoma specimens and in 6 (31.6%) small cell lung carcinoma specimens, whereas a similar frequency of LOH was statistically inferred to occur in cell lines by analyzing marker homozygosity as an indirect measure of LOH. Five specimens and 11 cell lines showed partial or interstitial deletions of chromosome 18q, and 2 of them had homozygous deletions at the 18q21.1 region. A commonly deleted region was assigned between the D18S46 and y953G12R loci. The size of this region is less than 1 Mb, and the coding exons of three candidate tumor suppressor genes, Smad2, Smad4, and DCC, were mapped outside the region. This result suggests that the common region harbors a novel tumor suppressor gene involved in the progression of lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau.

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer's disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid beta protein (Abeta1-42). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3beta (GSK-3beta). Deletion studies show that both tau and GSK-3beta bind to the same region of PS1, residues 250-298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3beta into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3beta. Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3beta and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3beta with mutant PS1 leads to increased phosphorylation of tau.

Adult↗
PubMed1998

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA.

The hOGG1 gene encodes a DNA glycosylase that excises 8-hydroxyguanine (oh8Gua) from damaged DNA. Structural analyses of the hOGG1 gene and its transcripts were performed in normal and lung cancer cells. Due to a genetic polymorphism at codon 326, hOGG1-Ser326 and hOGG1-Cys326 proteins were produced in human cells. Activity in the repair of oh8Gua was greater in hOGG1-Ser326 protein than in hOGG1-Cys326 protein in the complementation assay of an E. coli mutant defective in the repair of oh8Gua. Two isoforms of hOGG1 transcripts produced by alternative splicing encoded distinct hOGG1 proteins: one with and the other without a putative nuclear localization signal. Loss of heterozygosity at the hOGG1 locus was frequently (15/ 23, 62.2%) detected in lung cancer cells, and a cell line NCI-H526 had a mutation leading to the formation of the transcripts encoding a truncated hOGG1 protein. However, the oh8Gua levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed. These results suggest that the oh8Gua levels are maintained at a steady level, even though multiple hOGG1 proteins are produced due to genetic polymorphisms, mutations and alternative splicing of the hOGG1 gene.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

An improved method for the detection of changes in brain extracellular glutamate levels.

We developed a method for in vivo real-time monitoring of the concentration of extracellular glutamate ([Glu]e) in the brain under anoxic conditions. A dialysis electrode (Sycopel Int., UK) was employed as a sensing device to measure the concentration of glutamate by enzyme amperometry, and an electron mediator, ferrocene, was introduced into the electrode together with glutamate oxidase. The ferrocene was covalently conjugated with a high molecular weight molecule, bovine serum albumin, to avoid outward diffusion through the dialysis membrane. With this set-up, the amperometric response was independent of the pO2 around the electrode in vitro up to 400 microM glutamate. Using this method, we investigated the dynamics of [Glu]e in the rat striatum during anoxia. [Glu]e increased rapidly at 102+/-5.4s (n = 6) after the start of nitrogen inhalation. The increase continued for about 30 s, and then [Glu]e decreased. The peak value of delta[Glu]e was 141+/-37 micro M. [Glu]e subsequently underwent another gradual increase, reaching 213+/-69 microM at 15 min after the start of nitrogen inhalation. This distinct biphasic profile was reproducible. We conclude that this method is very useful for monitoring [Glu]e in the brain under low pO2 conditions.

Animals↗
PubMed1998

Interleukin-15 (IL-15) can replace the IL-2 signal in IL-2-dependent adult T-cell leukemia (ATL) cell lines: expression of IL-15 receptor alpha on ATL cells.

Interleukin-15 receptor (IL-15R) and IL-2R have the same beta and gamma chains, but IL-15R has a specific alpha chain distinct from that of IL-2Ralpha, which is indispensable for the high affinity binding of IL-15. In the present study, we examined four IL-2-dependent adult T-cell leukemia (ATL) cell lines for their IL-15R expression. All cell lines bound IL-15, which was not inhibited by a 100-fold excess amount of IL-2, proliferated in response to IL-15 to the same degree as to the stimulation with IL-2, and were maintained without IL-2. The responses to 1L-15 were inhibited by the antibodies against IL-2R beta or gamma chains but was not by the IL-2R alpha chain antibody. [125I]-IL-15 exhibited a single high-affinity binding with an apparent kd of 0.17 nmol/L. Reverse transcription-coupled polymerase chain reaction (RT-PCR) showed that the cell lines had the mRNA of IL-15R alpha. The cell lines also had IL-15 mRNA. Despite the presence of IL-15 mRNA, the cell lines did not secrete IL-15, and the culture supernatants of fresh ATL cells and plasma from the patients did not contain a detectable amount of IL-15 with a few exceptional cases, although fresh ATL cells also responded to IL-15. These results suggest that ATL cells have the complete form of IL-15R and respond to IL-15. Such an IL-15-dependent cell proliferation mechanism might be used in the development of ATL and for the invasion and proliferation of ATL cells in the visceral organs.

Adult↗
PubMed1998

G protein-bound conformation of mastoparan-X: heteronuclear multidimensional transferred nuclear overhauser effect analysis of peptide uniformly enriched with 13C and 15N.

Mastoparans, a family of tetradecapeptides from wasp venom, have been used as convenient low molecular weight models of receptors coupled to GTP-binding regulatory proteins (G proteins) for the understanding of the interaction between G proteins and receptors. Sukumar and Higashijima have analyzed the conformation of mastoparan-X (MP-X) bound to the G protein alpha-subunit using proton two-dimensional transferred nuclear Overhauser effect (TRNOE) spectroscopy [Sukumar, M., and Higashijima, T. (1992) J. Biol. Chem., 267, 21421-21424]. The resultant structure, however, was not well-defined due to severe overlap of peptide proton resonances. To determine the G protein-bound conformation of MP-X in detail, we have analyzed this interaction by heteronuclear multidimensional TRNOE experiments of MP-X uniformly enriched with 15N and/or 13C. By solving the overlap problem, we were able to determine the precise conformation of MP-X bound to Gi1alpha: the peptide adopts an amphiphilic alpha-helix from Trp3 to C-terminal Leu14, and the atomic root-mean-square deviation (rmsd) values in this portion about the averaged coordinates were 0.27 +/- 0.07 A for the backbone atoms (N, Calpha, C') and 0.84 +/- 0.16 A for all heavy atoms. These values are much smaller than the corresponding rmsd values of the structures obtained from the proton 2D TRNOE spectrum alone: 1.70 +/- 0.41 A for the backbone atoms (N, Calpha, C') and 2.84 +/- 0.51 A for all heavy atoms. Our results indicate that the heteronuclear multidimensional TRNOE experiments of peptides uniformly enriched with stable isotopes are a very powerful tool for analyzing the conformation of short peptides bound to large proteins. We will also discuss the structure-activity relationships of mastoparans in activating G proteins on the basis of the precise structure of MP-X bound to Gi1alpha.

Amino Acid Sequence↗
PubMed1998

Muscarinic facilitation of GABA release in substantia gelatinosa of the rat spinal dorsal horn.

1. Blind patch clamp recordings were made from substantia gelatinosa (SG) neurones in the adult rat spinal cord slice to study the mechanisms of cholinergic modulation of GABAergic inhibition. 2. In the majority of SG neurones tested, carbachol (10 microM) increased the frequency (677 % of control) of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs). A portion of these events appeared to result from the generation of spikes by GABAergic interneurones, since large amplitude IPSCs were eliminated by tetrodotoxin (1 microM). 3. The effect of carbachol on spontaneous IPSCs was mimicked by neostigmine, suggesting that GABAergic interneurones are under tonic regulation by cholinergic systems. 4. The frequency of GABAergic miniature IPSCs in the presence of tetrodotoxin (1 microM) was also increased by carbachol without affecting amplitude distribution, indicating that acetylcholine facilitates quantal release of GABA through presynaptic mechanisms. 5. Neither the M1 receptor agonist McN-A-343 (10-300 microM) nor the M2 receptor agonist, arecaidine (10-100 microM), mimicked the effects of carbachol. All effects of carbachol and neostigmine were antagonized by atropine (1 muM), while pirenzepine (100 nM), methoctramine (1 microM) and hexahydrosiladifenidol hydrochloride, p-fluoro-analog (100 nM) had no effect. 6. Focal stimulation of deep dorsal horn, but not dorsolateral funiculus, evoked a similar increase in IPSC frequency to that evoked by carbachol and neostigmine. The stimulation-induced facilitation of GABAergic transmission lasted for 2-3 min post stimulation, and the effect was antagonized by atropine (100 nM). 7. Our observations suggest that GABAergic interneurones possess muscarinic receptors on both axon terminals and somatodendritic sites, that the activation of these receptors increases the excitability of inhibitory interneurones and enhances GABA release in SG and that the GABAergic inhibitory system is further controlled by cholinergic neurones located in the deep dorsal horn. Those effects may be responsible for the antinociceptive action produced by the intrathecal administration of muscarinic agonists and acetylcholinesterase inhibitors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1998

Exposure to acute stress induces brain interleukin-1beta protein in the rat.

Peripheral immune stimulation such as that provided by lipopolysaccharide (LPS) has been reported to increase brain levels of IL-1beta mRNA, immunoreactivity, and bioactivity. Stressors produce many of the same neural and endocrine responses as those that follow LPS, but the impact of stressors on brain interleukin-1beta (IL-1beta) has not been systematically explored. An ELISA designed to detect IL-1beta was used to measure levels of IL-1beta protein in rat brain. Brain IL-1beta was explored after exposure to inescapable shock (IS; 100 1.6 mA tail shocks for 5 sec each) and LPS (1 mg/kg) as a positive control. Rats were killed either immediately or 2, 7, 24, or 48 hr after IS. Brains were dissected into hypothalamus, hippocampus, cerebellum, posterior cortex, and nucleus tractus solitarius regions. LPS produced widespread increases in brain IL-1beta, but IS did not. Adrenal glucocorticoids are known to suppress IL-1beta production in both the periphery and brain. Thus, it was possible that the stressor did provide stimulus input to the brain IL-1beta system(s), but that the production of IL-1beta protein was suppressed by the rapid and prolonged high levels of glucocorticoids produced by IS. To test this possibility rats were adrenalectomized or given sham surgery, with half of the adrenalectomized rats receiving corticosterone replacement to maintain basal corticosterone levels. IS produced large increases in brain IL-1beta protein in the adrenalectomized subjects 2 hr after stress, whether basal corticosterone levels had been maintained. Thus elimination of the stress-induced rise in corticosterone unmasked a robust and widespread increase in brain IL-1beta.

Acute Disease↗
PubMed1998

Alpha helix content of G protein alpha subunit is decreased upon activation by receptor mimetics.

To elucidate the mechanism whereby liganded receptor molecules enhance nucleotide exchange of GTP-binding regulatory proteins (G proteins), changes in the secondary structure of the recombinant Gi1 alpha subunit (Gi1alpha) upon binding with receptor mimetics, compound 48/80 and mastoparan, were analyzed by circular dichroism spectroscopy. Compound 48/80 enhanced the initial rate of GTPgammaS binding to soluble Gi1alpha 2.6-fold with an EC50 of 30 microg/ml. With the same EC50, the mimetic decreased the magnitude of ellipticity, which is ascribed to a reduction in alpha helix content of the Gi1alpha by 7%. Likewise, mastoparan also enhanced the rate of GTPgammaS binding by 3.0-fold and decreased the magnitude of ellipticity of Gi1alpha similar to compound 48/80. In corresponding experiments using a K349P-Gi1alpha, a Gi1alpha counterpart of the unc mutant in Gsalpha in which Pro was substituted for Lys349, enhancement of the GTPgammaS binding rate by both activators was quite small. In addition, compound 48/80 showed a negligible effect on the circular dichroism spectrum of the mutant. On the other hand, a proteolytic fragment of Gi1alpha lacking the N-terminal 29 residues was activated and showed decreased ellipticity upon interaction with the compound, as did the wild-type Gi1alpha. Taken together, our results strongly suggest that the activator-induced unwinding of the alpha helix of the G protein alpha subunit is mechanically coupled to the enhanced release of bound GDP from the alpha subunit.

Circular Dichroism↗
PubMed1998

Homozygous deletion and frequent allelic loss of the 21q11.1-q21.1 region including the ANA gene in human lung carcinoma.

The frequent occurrence of 21q deletions in human non-small cell lung carcinoma (NSCLC) indicates the presence of a tumor suppressor gene on this chromosome arm. Since the ANA (Abundant in Neuroepithelium Area) gene, a member of an antiproliferative gene family, was mapped to 21q11.2-q21.1, we searched for genetic alterations of the ANA gene in human lung cancers. The gene was homozygously deleted in a human NSCLC cell line, Ma17. The gene was mapped in the 0.33 Mb Not1 fragment at 21q21.1 of the Not1 restriction map for 21q. Loss of heterozygosity (LOH) at this locus was detected in 24/47 (51.1%) of NSCLC, and the frequency of LOH in brain metastases was significantly higher than that in stage I-II primary tumors (P = 0.018). These results suggested that the homozygously deleted region harbors a novel tumor suppressor gene involved in NSCLC progression. Since mutation of the ANA gene was not detected in other lung cancer cell lines and fresh lung tumors with LOH at this locus, it is unlikely that the ANA gene is a target gene inactivated by two mutational events in this chromosomal region. Physical mapping of the homozygously deleted region showed that the deletion had occurred interstitially at 21q11.1-q21.1 and the size of the deletion was estimated as being more than 3 Mb. Our mapping results will facilitate further efforts to identify a tumor suppressor gene on 21q.

Aged↗