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PubMed1996

Contact Effects of Mononuclear Cells on L929 Fibroblast Morphological Phenotype.

We studied the contact interactions of human peripheral blood mononuclear cells (MNC) and transformed mouse fibroblast cell line L929 (L-cells), namely their effects on morphological phenotype of L-cells. The morphological characteristics of the fibroblast, (cell area, nucleus-cytoplasmic ratio, cell spreading, cell shape) were estimated with the aid of fight scanning microscopy, followed by computer image analysis. Contact interaction between fibroblasts and MNC caused normalization of morphological phenotype of the fibroblasts (increase of cell area, shape factor, spreading and decrease of nucleus-cytoplasmic ratio). This phenomenon was revealed by analysis of both average morphological characteristics and population contents. Only a particular subpopulation of L-cells, but not the whole population, was shown to be normalized by the effects of MNC. For elucidation of responsible MNC population, which was capable of influencing on fibroblast morphological phenotype, we separated MNC in several cell types: adherent cells, non-adherent cells, which were separated in E-rosetting cells, and non-E-rosetting cells. Only non-adherent and E-rosetting cells could normalize the morphological phenotype. E-rosetting population consisted of 85% of CD3(+) (T lymphocytes) and 15percnt; of CD56(+)/CD16(+) (natural killers). Supernatants of MNC, and MNC cocultured L-cells, obtained after 24 h incubation in the cell culture medium, were not able to normalize the morphological phenotype of the fibroblasts. They had small denormalizing effect on the fibroblasts (decrease of cell area, shape factor, spreading and increase of nucleus-cytoplasmic ratio). The results of this study indicate that the contact interaction between MNC and fibroblasts may normalize transformed fibroblast morphological phenotype. The dependence of fibroblast functional state on their morphological phenotype imply the presence of regulatory mechanism of contact interaction between fibroblasts and MNC, which determines many live processes in fibroblast.

Journal Article↗

PubMedDate not supplied

Malignant potential regarding mucin phenotypes and endocrine cell differentiation in gastric adenocarcinoma.

BACKGROUND: This study was designed to define the relationship between the mucin phenotype and differentiation in endocrine cells, including their biological behavior in gastric adenocarcinoma. MATERIALS AND METHODS: A total of 337 cases of solitary gastric adenocarcinoma were studied. The depth of tumor invasion was the mucosa in 58 cases, the submucosa in 206 cases and the muscularis propria in 73 cases. The mucin phenotype was divided into four phenotypes (gastric, intestinal, mixed and null types) based on immunohistochemical staining (HGM, Muc2 and CD10) and histochemical staining (PCS). Endocrine cells were identified by immunohistochemical staining (serotonin, gastrin, pancreatic polypeptide and Chromogranin A staining) in order to examine their relationship to mucin phenotype. Lymph node metastasis was used as a major indicator of the malignant potential. RESULTS: When lymph node metastasis was analyzed for tumors with submucosa(sm) or muscularis propria invasion, the incidence was significantly higher in the endocrine cell-positive [ECs(+)] group than in the endocrine cell-negative [ECs(-)] group. Namely, in gastric type, the incidence was 22.7% for the ECs(+) group and 0% for the ECs(-) group (p < 0.05). In intestinal type it was 26.9% for the ECs(+) group and 4.5% for the ECs(-) group (p < 0.05). When the 5-year survival rate of patients with a depth of sm or mp carcinoma was analyzed in relation to the mucin phenotype, no significant difference was seen in the survival rate according to the mucin phenotype, but the prognosis tended to be less favorable in the ECs(+) group than in the ECs(-) group (p = 0.06). CONCLUSION: The expression of endocrine cells was thus found to be more important as a prognostic factor than the mucin phenotype.

Adenocarcinoma↗

PubMed1992

Characterization of B-cell phenotypic changes during ileal and jejunal Peyer's patch development in sheep.

Changes in B-cell phenotype during development of ileal and jejunal Peyer's patches (PP) of sheep were investigated using flow cytometry and immunoperoxidase-stained cryosections. On Day 104 of gestation (term at 150 days) B-cell clusters were identified in the lamina propria of the ileum. These clusters were composed of cells that expressed surface IgM (sIgM), lambda or kappa light chain, and BAQ44A, a B-cell differentiation molecule. No cells in the clusters stained for terminal deoxynucleotide transferase. On Day 132 gestation, a change was evident in the phenotype of ileal PP B cells. Most B cells expressed a reduced level of sIgM and 20% were BAQ44A-. The B cells in the dome region were BAQ44A+ but few BAQ44A+ cells were present in the follicles. At 6-8 weeks of age BAQ44A+ cells were restricted to the dome region of the ileal PP; flow cytometric analysis confirmed that 25% of B cells isolated from the dome/follicle complex were BAQ44A+. Thus, the primordial PP was populated with B cells that were phenotypically similar to circulating B cells (sIgMhigh, BAQ44A+). After 132 days gestation, the predominant B-cell phenotype in the ileal PP changed to sIgMlow and BAQ44A-. This phenotypic change could be the result of either early immigrant B-cell differentiation or subsequent colonization by sIgMlow BAQ44A- B cells. The phenotypic changes of ileal PP follicular B cells were not complete until after birth and different phenotypic changes were observed in follicles of the jejunal PP of young lambs.

Animals↗

PubMed2005

Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a "non-germinal center phenotype".

Amplification and translocation of the Bcl-2 gene has been detected in a certain subset of diffuse large B-cell lymphomas (DLBCL). The correlations among Bcl-2 protein expression, gene translocation or amplification, and the molecular signature determined by cDNA array are poorly understood. This study examined 25 cases with de novo nodal DLBCL. Interphase fluorescence in situ hybridization (FISH) analysis was performed to evaluate the Bcl-2 gene using IGH/BCL2 and CEP18 centromere probes (Vysis). When extra Bcl-2 gene signals were observed in each tumor cell and when these signals were in proportion to the extra CEP18 probe signals, we regarded the findings as indicating the presence of an additional chromosome 18; when extra Bcl-2 signals were observed but additional CEP18 signals were not, we regarded the findings as indicating the presence of gene amplification. A panel of 3 antigens (CD10, Bcl-6, and MUM-1) was applied to categorize each case as either a "germinal center B-cell (GCB) phenotype" or a "non-GCB phenotype." Of the 25 cases examined, 8 cases (32%) were classified as "GCB phenotype" and 17 cases (68%) were classified as "non-GCB phenotype." A FISH analysis revealed that t(14;18) was detected in 2 of the 8 cases (25%) with the "GCB phenotype" but in none of the 17 "non-GCB phenotype" cases. Extra Bcl-2 gene signals were detected in 7 of the 25 (28%) cases examined: n = 5 for an additional chromosome 18, n = 1 for gene amplification, and n = 1 for additional chromosome 18 + gene amplification. Extra Bcl-2 gene signals were exclusively detected in DLBCL with the "non-GCB phenotype"; these cases, with the exception of one, stained strongly positive for Bcl-2. The DLBCLs with Bcl-2 protein overexpression were classified into at least two heterogeneous molecular groups, based on the results of the FISH analysis.

Adult↗

PubMed2005

[Flow cytometric detection of minimal residual disease in pre-cursor-B-acute lymphoblastic leukemia on the basis of phenotypic aberrancies on minor leukemic cell populations].

To test the European BIOMED-1 Concerted Action proposed technique to detect minimal residual disease (MRD) in the chinese patients with precursor-B-acute lymphoblastic leukemia (precursor-B-ALL) by triple-staining flow cytometry and to define both normal and aberrant phenotypic profiles of precursor B cells, a series of bone marrow samples, 35 from precursor-B-ALL (13 in newly diagnosed cases, 15 at the end of remission induction therapy and 7 at end of the consolidations), and 19 from normal controls, were immunophenotyped with the five triple-staining antibodies (TdT/CD10/CD19, CD10/CD20/CD19, CD34/CD38/CD19, CD34/CD22/CD19 and CD19/CD34/CD45) recom-mended by the BIOMED-1 using common flow cytometric protocols. Further, with different ratios of the leukemic cells with CD34/CD38/CD19 phenotype and normal mononuclear cells, a serial dilution test was analyzed. The results showed that three major CD19(+) cell subpopulations were identified in the normal controls, representing three consecutive maturation stages. The subpopulations in the precursor-B-ALL cases disappeared and were replaced with a great number of luekemic cells which had different characteristics of phenotypes, and then they reappeared with almost same characteristics as the normal CD19(+) cells after the patients achieved complete remission. When the five triple-staining antibody combinations were used, the phenotypic aberrancies could be identified in 12/13 (92.3%) cases with newly diagnosed precursor-B-ALL, at least one triple-labeling per case at the level of 0.01% or more. The frequencies of phenotypic aberrations detected with the triple-staining were 8/13 (61.5%) for CD10/CD20/CD19, 5/13 (38.5%) for CD34/CD38/CD19, 4/13 (30.8%) for CD10/TdT/CD19, 3/13 (23.1%) for CD34/CD22/CD19, and 2/13 (15.4%) for CD34/CD45/CD19. At the end of remission induction, the phenotypic aberrancies could be detected in 5/15 (33.3%), of which, 3/8 (37.5%) cases with the leukemic phenotypes detected both at the newly diagnosis and at the end of induction. The dilution test indicated that the cells with CD34/CD38/CD19 detected by flow cytometry correlated well with the leukemic cells added (r = 0.85, P < 0.05) over 1:1 to 1:400,000. It is concluded that the flow cytometric detection of precursor-B-ALL-MRD proposed by BIOMED-1 Concerted Action were well realized in this study. The one precursor-B-ALL cell can be effectively detected out of 10(4) normal bone marrow cells.

Adolescent↗

PubMed1986

Phenotypic analysis of thymocytes that express homing receptors for peripheral lymph nodes.

Thymocytes that express high levels of homing receptors for peripheral lymph nodes can be detected with the monoclonal antibody MEL-14. We have shown that in adult mice these rare MEL-14hi thymocytes a) are cortical in location and typically constitute 1 to 3% of the total thymocyte population, b) may be a major source of thymus emigrants, and c) contain a high frequency of precursors of alloreactive cytotoxic T lymphocytes. In this study we have analyzed the phenotype of the MEL-14hi thymocyte subset. Most normal adult MEL-14hi thymocytes are midsize and express the mature phenotype typical of thymus emigrants, medullary thymocytes, and peripheral T cells: they are predominantly PNAlo, H-2K+, Thy-1+, Ly-1hi, and either Lyt-2-/L3T4+ or Lyt-2+/L3T4-. These findings argue strongly for the presence of rare MEL-14hi immunocompetent cortical thymocytes that, aside from their homing receptor expression, are phenotypically indistinguishable from medullary thymocytes. However, a minority (20 to 30%) of MEL-14hi thymocytes are large and phenotypically nonmature: they express intermediate to high levels of PNA binding sites, and are H-2K- to H-2Klo, Thy-1hi, Ly-1+, and either Lyt-2+/L3T4+ or Lyt-2-/L3T4-. Through a technique that selectively labels outer cortical cells, phenotypically nonmature MEL-14hi thymocytes have been shown to be concentrated in the subcapsular blast region of the outer cortex. Although we have no direct evidence of a precursor-product relationship, we consider it likely that the phenotypically nonmature outer cortical MEL-14hi lymphoblasts give rise to phenotypically mature MEL-14hi cells located deeper in the cortex. These results are consistent with our previous proposal that MEL-14hi thymocytes are a major source of thymus emigrants, and indicate that expression of high levels of MEL-14-defined homing receptors may be closely linked to the intrathymic selection process.

Animals↗

PubMed1998

Phenotypic characterization of septal neurons in culture: immunohistochemistry of GABA, calbindin D-28k and choline acetyltransferase, and histochemistry of acetylcholinesterase

Phenotypes of septal neurons, dissociated from 19-day-old fetal rat brains and then cultured in a medium containing nerve growth factor for 4 weeks, were examined using gamma-aminobutyric acid (GABA), calbindin D-28k, parvalbumin and choline acetyltransferase immunohistochemistry, and acetylcholinesterase histochemistry. There were primarily four groups of neurons identified in this septal culture: the first group (12.7% of 212 neurons examined) displayed a cholinergic, but not GABAergic, phenotype and had an average diameter of 13.6±2.7 μm (mean±S.D.); the second group (31.6%) displayed both cholinergic and GABAergic phenotypes and had a diameter of 12.2±2.8 μm; the third group (31.0%) displayed only a GABAergic phenotype and had a diameter of 10.4±2.3 μm; and the fourth group (24.7%) displayed neither a GABAergic nor cholinergic phenotype and had a diameter of 10.4±2.1 μm. Neurons in the first two groups described were significantly larger than those in the second two groups; neurons in the third and fourth groups were the same size. Calbindin D-28k was expressed in some neurons of each group (31.3%, 18.8%, 9.6% and 15.7%, respectively). These results demonstrate that septal neurons have the ability to express a variety of phenotypes when grown in vitro. This culture will be a useful tool for studying mechanisms of phenotype expression in septal neurons.

Journal Article↗

PubMed2026

Dental phenotypes associated with novel PHEX variants in X-linked hypophosphatemia.

OBJECTIVES: X-linked hypophosphatemia (XLH) is a genetic disorder related to bone, mainly due to the mutations in PHEX gene. Previous studies have reported that XLH patients had various tooth phenotypes. It is unclear whether there are any rules about these abnormal tooth phenotypes, especially in those XLH cases with PHEX mutations. The objectives of this study were to find the most representative dental characteristics of XLH and the possible phenotype-genotype correlation. DESIGN: Two unrelated patients with XLH underwent clinical, radiographic, biochemical, and genetic evaluation. Whole-exome sequencing and whole-genome sequencing were used to identify pathogenic variants. The ultrastructure of extracted teeth was analyzed using a stereomicroscope, micro-CT, and scanning electron microscopy. In addition, a PubMed search (up to January 2026) identified 22 articles involving 366 patients for descriptive phenotype comparison. RESULTS: Two novel PHEX variants were identified: a novel complex structural variant (NC_000023.11, g.22035649-22041668delins) and a novel heterozygous splice-site variant (NM_000444.6, c.850-1 G>A). Radiographic examination showed enlarged pulp chambers and irregular pulp morphology. Ultrastructural analysis revealed dentin defects, including globular dentin, irregular interglobular dentin, disrupted dentinal tubules, and exposed collagen fibrils. Literature-based analysis indicated prevalent clinical manifestations (pulp necrosis, tooth loss, periodontitis) and radiographic findings (enlarged pulp chamber, and prominent pulp horn). CONCLUSION: In these two patients, novel PHEX variants were associated with a recurrent dentin-pulp phenotype. Integrated clinical, radiographic, ultrastructural, and literature evidence supports dentin defects as a central component of the dental phenotype in XLH and underscores the importance of early dental assessment.

Humans↗

PubMed2026

Causal relationships between oral-gut microbiome and bone neoplasm-related phenotypes: Insights from bidirectional Mendelian randomization.

The human oral and gut microbiota are the 4 largest microbial communities in the body and play crucial roles in maintaining homeostasis and influencing disease. Observational studies have suggested links between these microbiota and bone neoplasm-related phenotypes, but establishing causality has been challenging due to confounding factors and reverse causality. We conducted a bidirectional, 2-sample Mendelian randomization (MR) study to investigate evidence consistent with a potential causal association between the saliva and gut microbiota and various bone neoplasm-related phenotypes. Genetic instruments for saliva and gut microbiota were sourced from large genome-wide association studies. Inverse variance weighted was the primary MR method, supplemented by 4 other MR techniques. Sensitivity analyses, including MR-Egger regression, were performed to assess pleiotropy and heterogeneity. In the forward MR analysis, Veillonella parvula from the saliva microbiota was associated with a decreased risk of bone and connective tissue neoplasms (β: -0.236, 95% CI: [-0.275, -0.197], P = 8.20E-33). MR analyses identified genetically predicted associations between several microbial taxa and bone neoplasm-related phenotypes. Reverse MR analyses showed that genetic liability to bone neoplasm-related phenotypes was associated with variation in the composition of the oral (e.g., Order Bacteroidales, Rothia mucilaginosa) and gut microbiota (e.g., Class Methanobacteria, Genus Eubacterium oxidoreducens group). Sensitivity analyses confirmed the robustness of these findings, as no statistical evidence of substantial heterogeneity or directional horizontal pleiotropy was detected. This study provides genetic evidence supporting a bidirectional causal relationship between specific saliva and gut microbiota and bone neoplasm-related phenotypes. Our findings identify several microbial taxa as potential candidates for future biomarker development and therapeutic investigation in bone neoplasm-related phenotypes. However, these genetically informed associations require further mechanistic, experimental, and prospective clinical validation before clinical application.

Humans↗

PubMed2024

Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant.

BACKGROUND: Androgen insensitivity syndrome (AIS) is a rare genetic disorder characterized by resistance to androgens, mainly due to mutations in the androgen receptor (AR) gene. It can manifest as complete AIS, partial AIS and mild AIS. While there have been studies linking specific AR gene mutations to AIS phenotypes, different clinical AIS phenotypes are also reported in patients with the same AR gene mutation. So far, the precise correlations between phenotypes and genotypes remain incompletely understood. METHODS: We conducted a thorough investigation involving four patients diagnosed with different types of AIS from a single Chinese family. Clinical manifestations, laboratory examinations, and fertility outcomes were well-documented. Furthermore, we performed genetic sequencing to detect possible pathogenetic variants. RESULTS: Whole exome sequencing identified a hemizygous missense variant (c.2263T > C; p.Phe755Leu) of AR gene in all four affected patients with different degrees of undermasculinisation and heterogeneous spermatogenesis. The proband, diagnosed with partial AIS, opted for treatment with donated sperm due to non-obstructive azoospermia, while their older sibling, diagnosed with complete AIS, was raised as a girl. His two maternal uncles were both diagnosed with mild AIS, the older uncle fathered two girls naturally, whereas the younger uncle utilized assisted reproductive technology to conceive a boy because of severe oligoasthenozoospermia. CONCLUSION: Our study first identified the same AR variant (c.2263T > C;p.Phe755Leu) in four affected patients displaying highly diverse phenotypes of AIS and fertility outcomes, thereby significantly expanding the phenotypic spectrum of AIS. Notably, we presented a clear insight into different fertility outcomes of AIS patients with identical AR (c.2263T > C;p.Phe755Leu) variant, which provided reliable evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology. Furthermore, our study underscored the potential role of androgen concentration in shaping the phenotypic diversity of AIS, warranting further investigation.

Adult↗

PubMed2025

Distinct immune-metabolic phenotypes underlie poor coronary collateral circulation.

BACKGROUND: Coronary collateral circulation (CCC) significantly impacts myocardial perfusion and clinical outcomes in coronary artery disease patients, yet the underlying molecular heterogeneity remains inadequately characterized. OBJECTIVE: To identify distinct molecular phenotypes in patients with poor CCC, validate these phenotypes using clinical parameters, and evaluate their prognostic implications. METHODS: This study enrolled 149 patients (80 with good CCC and 69 with poor CCC) for high-throughput proteomic profiling. Unsupervised consensus clustering identified molecular subtypes within poor CCC patients, followed by differential expression analysis and KEGG pathway enrichment. Boruta feature selection was implemented, and multiple machine learning algorithms were tested on clinical data, with XGBoost optimization (accuracy 80.0%, F1-score 80.31%) and SHAP value interpretation. External validation was performed using the MIMIC database. Kaplan-Meier analysis and Cox regression models assessed major adverse cardiovascular events (MACE). RESULTS: Two distinct phenotypes emerged among poor CCC patients: Cluster 1 (n = 39, Complement-Driven Vascular Remodeling [CDVR]) and Cluster 2 (n = 30, Immuno-Thrombotic Myocardial Dysfunction [ITMD]). An XGBoost model incorporating fasting glucose, eosinophil percentage, and HbA1c achieved excellent discrimination (AUC > 0.91). External validation confirmed the phenotype-specific clinical patterns. Notably, Cluster 2 demonstrated significantly higher MACE incidence compared to Cluster 1 (Log-rank p < 0.05), with KEGG analysis revealing significant upregulation of platelet activation, diabetic cardiomyopathy, and metabolic pathways in the ITMD phenotype. CONCLUSION: Poor CCC encompasses distinct immune-metabolic phenotypes that can be accurately classified using integrated proteomic-clinical modeling. This classification enables more precise risk stratification and may guide personalized therapeutic strategies for coronary artery disease patients with inadequate collateralization.

Humans↗

PubMed1996

Apolipoprotein E phenotype frequency and cerebrospinal fluid concentration are not associated with Creutzfeldt-Jakob disease.

OBJECTIVE: To analyze the distribution of apolipoprotein E (Apo E) phenotypes between patients with Creutzfeldt-Jakob disease (CJD) and control subjects. SETTING: University hospital, base of the German National CJD Surveillance Study. DESIGN: Prospective case-control study. SUBJECTS: Sixty-two patients with definite or probable CJD, 90 patients with initial suspected CJO, and 51 controls matched for age, sex, and place of residence. MAIN OUTCOME MEASURES: Phenotyping of Apo E in serum by isoelectric focusing, assessment of the gels by 3 independent investigators, measurement of of Apo E in cerebrospinal fluid using an enzyme-linked immunosorbent assay, and calculation of Kaplan-Meier cumulative survival plots. RESULTS: The most frequent phenotype was E 3-3 with 56% in patients and 59% in controls, followed by E 3-4 with a frequency of 29% vs 25%, respectively. The phenotype E 3-2 was much rarer (13% vs 16%, respectively). Patients with definite CJD had a mean (SD) Apo E concentration of 3.4 (2.0) mg/L; patients with probable CJD, 3.1 (1.6) mg/L; patients with possible CJD, 3.8 (2.2) mg/L; and subjects with other diseases, 3.0 (1.7) mg/L. Mean (SD) disease duration for patients with E 3-2 was 11.8 (9.8) months; for patients with E 3-3, 12.0 (9.02) months; and for patients with E 3-4, 14.2 (12.3) months. CONCLUSIONS: We found no significant difference in the distribution of Apo E phenotypes between patients with CJD and controls. The concentration of Apo E in cerebrospinal fluid cannot be taken as a biochemical marker for the disease. The Apo E phenotype had no influence on the duration of CJD. Our data do not support an association of Apo E4 with either the duration or time at onset of CJD.

Adult↗

PubMed1999

Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.

BACKGROUND: X-linked adrenoleukodystrophy (ALD) is an inherited disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. The classic form of ALD usually has onset in childhood (childhood cerebral ALD), with rapid neurologic deterioration leading to a vegetative state. Adult-onset cerebral ALD also presents with rapidly progressive neurologic dysfunction. Milder phenotypes such as adrenomyeloneuropathy and Addison disease only also have been recognized. Despite discovery of the causative gene, a molecular basis for the diverse clinical presentations remains to be elucidated. OBJECTIVES: To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutations in this gene, and to study genotype-phenotype correlations in Japanese patients. METHODS: The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyeloneuropathy. We conducted detailed mutational analyses of 29 unrelated Japanese patients with ALD by genomic Southern blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction products derived from total RNA that was extracted from cultured skin fibroblasts, lymphoblastoid cells, or peripheral blood leukocytes. RESULTS: Three patients with adult-onset cerebral ALD were identified as having large genomic rearrangements. The remaining 26 patients were identified as having 21 independent mutations, including 12 novel mutations resulting in small nucleotide alterations in the ALD gene. Eighteen (69%) of 26 mutations were missense mutations. Most missense mutations involved amino acids conserved in homologous gene products, including PMP70, mALDRP, and Pxa1p. The AG dinucleotide deletion at position 1081-1082, which has been reported previously to be the most common mutation in white patients (12%-17%), was also identified as the most common mutation in Japanese patients (12%). All phenotypes were associated with mutations resulting in protein truncation or subtle amino acid changes. There were no differences in phenotypic expressions between missense mutations involving conserved amino acids and those involving nonconserved amino acids. CONCLUSIONS: There are no obvious correlations between the phenotypes of patients with ALD and their genotypes, suggesting that other genetic or environmental factors modify the phenotypic expressions of ALD.

Adolescent↗

PubMed1996

Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.

Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5 alpha-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5 alpha-reductase 2 deficiency (SRD). Phenotypes, which were classified according to the severity of the masculinization defect, varied between completely female (SRD type 5), predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male with micropenis and hypospadias (SRD type 2), and completely male without overt signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased ( > 50) in the classical syndrome (SRD type 5), but variable in the less severe affected patients (SRD types 1-4) (14-35). Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5 alpha-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1998

No evidence of replication error phenotype in primary gastric lymphoma of mucosa-associated lymphoid tissue.

Replication error (RER) phenotype, caused by deficiency of DNA mismatch repair genes and revealed by widespread microsatellite instability, has been detected in subsets of a wide variety of solid tumors, but rarely in lymphomas in general. So far, the involvement of RER phenotype in the pathogenesis of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type has not been conclusively established. We therefore examined 9 microsatellite loci on 5 chromosomes [D2S123, D3S11, D3S1261, D3S1262, D3S1265, D6S262, D18S559, a CTTT(T) repeat in intron 20 of RBI gene and a CA repeat in p53 locus] in 33 cases of primary gastric MALT lymphoma for evidence of microsatellite instability by polymerase chain reaction using primers end-labeled with [gamma-33P] ATP. Although novel-length allele was observed in 7 of 33 cases (21.2%), none of these 7 cases showed changes in more than one locus. RER phenotype was scored as positive in a case when more than 1 of the 9 examined microsatellite loci showed length alterations. Accordingly, none of the 33 cases had a RER phenotype. This result suggests that the pathogenesis of gastric MALT lymphoma does not involve RER phenotype. It is consistent with the general observations in lymphomas, but is highly in contrast to a previous report showing more than 50% of MALT lymphomas with the RER phenotype.

DNA Ligases↗

PubMed1997

Apolipoprotein E phenotype, arterial disease, and mortality among older women: the study of osteoporotic fractures.

This study is an investigation of the relationship between apolipoprotein E (apoE) phenotype, arterial disease, and mortality in a group of women (n = 1,751) aged 65 years and older enrolled in the Study of Osteoporotic Fractures. Crude mortality rates were highest among women with the 4-3 and 4-4 phenotypes but age-adjusted mortality showed no statistically significant variations across the phenotype groups. Using multivariate analysis, the mortality experience of women with 4-3 or 4-4 apoE phenotypes was compared to that of women with the 3-3 phenotype: no significant excess total mortality was found [relative risk (RR) = 1.2, 95% confidence interval (CI) 0.8, 1.8] among women with the epsilon 4 allele. Similarly, neither cardiovascular (RR = 0.9. 95% CI 0.5, 1.8) nor cancer (RR = 1.5, 95% CI 0.8, 2.8) mortality rates were significantly different in this group of women. Inclusion of cholesterol levels in the regression models did not change the relative mortality risks. Among women 65-69 year of age epsilon 4 was associated with an approximate doubling of RR for death due to both cardiovascular disease and cancer. No association was found between apoE phenotype and the presence of lower extremity arterial disease (defined as an ankle/arm index of 0.9 or less). These results suggest that women with the epsilon 4 who survive to age 70 years or beyond have a life expectancy that is similar to that for women homozygous for the 3 allele who comprise the majority of the population.

Aged↗

PubMed2000

Cellular phenotypes of differentiated-type adenocarcinomas and precancerous lesions of the stomach are dependent on the genetic pathways.

To elucidate the relationship between genetic alterations and cellular phenotypes in differentiated-type carcinomas and precancerous lesions of the stomach, mutations of p53, APC and K-ras genes were examined, as well as microsatellite instability (MSI), in 52 tumours of the stomach. Tumours were selected with the following phenotypical features, using mucin histochemical and immunohistochemical analyses, in addition to their morphological features: (1) tumours with an extremely well-preserved gastric foveolar phenotype (foveolar-type); (2) tumours with an extremely well-preserved complete-type intestinal metaplastic phenotype (CIM-type); and (3) ordinary tumours without extreme phenotypes (ordinary-type). MSI occurred in 45% of foveolar-type, 24% of ordinary-type, and 0% of CIM-type tumours. p53 gene alterations occurred in 5% of foveolar-type, 18% of ordinary-type, and 31% of CIM-type. APC gene alterations were detected in 9% of foveolar-type, 6% of ordinary-type, and 0% of CIM-type. No K-ras gene mutation was detected in any of the three types. These results indicate that the genetic pathways are quite different among the phenotypes of tumours of the stomach. The 'mutator pathway', characterized by MSI, plays an important role in the tumourigenesis of foveolar-type, but not CIM-type tumours. The 'suppressor pathway', represented by p53 alteration, could participate in the tumourigenesis of the CIM-type, but is rare in foveolar-type tumours.

Adenocarcinoma↗

PubMed1988

Phenotypic heterogeneity of erythroblasts in erythroblastic leukemia revealed by monoclonal antibodies.

Eight cases each of erythroleukemia (AML-M6) and erythroblastic crisis of chronic granulocytic leukemia (CGLBC-E) were immunophenotyped with the help of a panel of lineage-associated monoclonal antibodies (McAbs). The latter included those reactive with erythroid progenitor (BFU-E and CFU-E) and erythroid precursors at different stages of maturation. In six of eight cases of AML-M6, erythroblasts revealed an immature phenotype, as evident from reactivity of the blast cells with McAbs directed against the earlier stages of erythroid maturation. One case had the phenotype of CFU-E, and in the remaining case of AML-M6 the erythroblasts showed a "mature" surface antigenic profile. This immunophenotypic spectrum was unrelated to the morphologic maturity of the erythroblasts. In two cases of CGLBC-E, an early erythroblastic phenotype was observed, while in as many cases a "mature" phenotype was present. Four of eight cases, however, revealed a mixed, erythroid plus myeloid phenotype. In one of the four cases, two separate blast populations, which represented erythroblasts and myeloblasts, could be identified. In the remaining three cases the blasts were morphologically homogeneous and undifferentiated. High incidence of HLA-DR positivity in the latter three cases suggests the primitive nature of blasts cells and their closeness to the putative "bipotent" myeloid stem cell. Our study has shown phenotypic heterogeneity of blast cells in AML-M6 and CGLBC-E.

Antibodies, Monoclonal↗