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Results for “phenotypic heterogeneity”

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At least 19 recordsLinked to original sources
PubMed2005

Dissection of heterogeneous phenotypes for quantitative trait mapping.

We discuss analyses of Genetic Analysis Workshop 14 data from the Collaborative Study on the Genetics of Alcoholism (COGA) as well as from a simulated complex disease, Kofendrerd personality disorder (KPD), with both genetic and phenotypic heterogeneity. Both data sets included numerous related phenotypes in addition to disease definitions. All analyses either chose from the given selection of phenotypes or defined new ones, including traits that may not have been related to alcoholism or KPD. Some contributors evaluated the genetic components of the trait. Many investigated genome-wide linkage and/or association, using microsatellites and/or single-nucleotide polymorphism (SNP) chip data. Here we will focus on methodological issues that the investigators faced. Their results depended on phenotype selection, whether continuous or discrete, the covariates included, and ethnicity of the study population. For SNP chip data, members of our group detected no difference in results for Affymetrix or Illumina chips, although higher marker density for association studies appeared to be advantageous. Overall, there were some observations that different chromosomal segments, i.e., physical locations on the p-arm, q-arm, or middle segment, might lead to possible differences in type I error rates. This finding and others highlight the importance of empirical determination of P-values to determine significance.

Alcoholism↗
PubMed2007

Microbial phenotypic heterogeneity and antibiotic tolerance.

Phenotypic heterogeneity, defined as metastable variation in cellular parameters generated by epigenetic mechanisms, is crucial for the persistence of bacterial populations under fluctuating selective pressures. Diversity ensures that some individuals will survive a potentially lethal stress, such as an antibiotic, that would otherwise obliterate the entire population. The refractoriness of bacterial infections to antibiotic therapy has been ascribed to antibiotic-tolerant variants known as 'persisters'. The persisters are not drug-resistant mutants and it is unclear why they survive antibiotic pressure that kills their genetically identical siblings. Recent conceptual and technological advances are beginning to yield some surprising new insights into the mechanistic basis of this clinically important manifestation of phenotypic heterogeneity.

Anti-Bacterial Agents↗
PubMed1989

[Ultrastructural evaluation of pulmonary adenocarcinoma. II. Phenotype heterogeneity and classification].

A phenotypical heterogeneity was observed in 45 tumours (45 per cent) from a group of 102 carcinomas with ultrastructural features of exocrine differentiation. Double heterogeneity was found in 36 tumours and a triple one in 8 tumours; a case with quadruple heterogeneity was presented analogy of which has been lacking in literature. A combination of different exocrine phenotypes occurred in 12 tumours, exocrine and endocrine phenotypes combined in 18 tumours, exocrine cells and keratinocytes were found in 21 tumours. The exocrine phenotype was characterized usually (38 times) by secretion granules mostly of a serous type (19 times), cells with microvillous specialization without granules represented (15 times) a lower level of the exocrine phenotypical differentiation. A ciliary phenotype which could not produce homogenous population of dividing cells yet occurred (4 times) as a rudimentary accompaniment of an endocrine phenotype. The case of quadruple heterogeneity combined ciliary, serous, endocrine and keratinocytic phenotypes. The WHO histological typing scheme does not offer a proper category for heterogenous adenocarcinomas with one prevailing exocrine phenotype when compared with an analogous group of "combined" small cell carcinomas. Histological typing of such heterogenous adenocarcinomas is to be completed at least by an electron microscopical prevailing cytological characteristic in the same way as in phenotypically homogenous carcinomas. Heterogenous tumours without any phenotypical prevalence may form a group of mixed carcinomas which has been represented so far only by the histological types of adenosquamous and mucoepidermoid carcinoma.

Adenocarcinoma↗
PubMed2004

Phenotypic heterogeneity in AAAS gene mutation.

UNLABELLED: We report the cases of two sibs of North African origin with AAAS gene mutation characterized by the heterogeneity of their phenotype. While an 8-y-old boy presented with acute adrenal insufficiency and mental retardation, the diagnosis was suggested by the clinical history of his 6-y-old sister who had symptomatic achalasia and chronic adrenal failure. CONCLUSION: Our observations corroborate the phenotypic heterogeneity reported in triple A syndrome, and underline the possibility of a variable intra-familial expression.

Adrenal Insufficiency↗
PubMed1987

Phenotypic heterogeneity of melanoma. Relation to the differentiation program of melanoma cells.

Phenotypic heterogeneity is a characteristic feature of tumor lesions in patients with melanoma. Variability can be observed in cell morphology, pigmentation, and antigen expression. To test whether phenotypic heterogeneity could be the result of events regulated during cell differentiation, we evaluated the expression of a panel of differentiation traits on melanoma cells. Metastatic melanoma lesions from two patients, designated FD and AP, were examined histologically and found to contain mixed populations of cells. Established melanoma cell lines derived from each of these lesions were subcloned at early passage in culture (passages 7 and 8) to create a panel of clones derived from each tumor. There was heterogeneity in the expression of differentiation-related traits in clones, corresponding to distinct phenotypes observed within the original tumors. Clones from patient FD corresponded to early to intermediate stages of melanocyte differentiation, and clones from patient AP ranged from intermediate to late stages. The influence of cholera toxin and PMA on differentiation of parental cultures and subclone was studied. Results of induction studies demonstrated a number of features of differentiation of melanoma cells: regulation of differentiation traits is coordinated as a program of traits expressed sequentially at specific stages; early traits, such as the epidermal growth factor receptor and the melanoma chondroitin sulfate proteoglycan antigen, are downregulated as melanoma cells differentiate, whereas late markers, including melanin, tyrosinase activity, and antigens expressed in mature melanosomes, are upregulated; Ia (class II major histocompatibility) antigens are characteristically expressed on melanomas corresponding to early or intermediate stages of differentiation and are regulated as part of the differentiation program; minimal changes in stage of differentiation were observed during induction of parental cultures with either cholera toxin or PMA, whereas definite shifts in differentiation could be induced in selected cloned subpopulations. We conclude that melanoma cells are not frozen at a specific stage of differentiation, but rather are capable of differentiating when exposed to appropriate signals. Diversity in the differentiation state of melanoma cells can account for much of the phenotypic heterogeneity observed in melanoma lesions.

Antigens, Neoplasm↗
PubMed2004

Immunophenotype and possible origin of nevi with phenotypical heterogeneity.

Biphenotypical nevi or nevi with phenotypical heterogeneity consist of phenotypically different cell populations in a pattern other than that observed in classical combined nevi or in various maturation stages of banal nevocellular nevi. Besides several well-known entities such as deep penetrating nevi and plexiform spindle cell nevi, this category of pigment cell lesions also harbors fewer delineated lesions such as nevi with atypical dermal nodules (N-ADN) and nevi with a focal atypical epithelioid cell component (N-FAECC). Their worrisome histology may result in a wrong diagnosis of malignancy. In order to discriminate them from malignant melanoma and to shed light on their histogenesis, we analyzed the immunophenotypical profile of 33 N-FAECC, 6 N-ADN, and 10 giant congenital nevi removed shortly after birth, using antibodies directed to S100 protein, gp100, tyrosinase, NKI-C3, Melan-A and Mib-1. In N-FAECC and N-ADN, the large polygonal cells expressed gp100, S100 protein and Melan-A, and reacted with monoclonal antibody NKI-C3. In addition, there was intense tyrosinase expression but no Mib-1 immunoreactivity. Unexpectedly, we observed similar single or clustered, large epithelioid cells in three out of ten giant congenital nevi; these cells showed a similar phenotype to those observed in N-ADN and N-FAECC. Our histological and immunohistochemical data suggest that N-FAECC and N-ADN may reflect different stages of the same disorder. Moreover, their resemblance to the large polygonal cells in congenital nevi may suggest that the histogenesis of N-ADN and N-FAECC may be related to the persistence and expansion of large epithelioid cells in congenital nevi shortly after birth.

Antigens, Neoplasm↗
PubMed1991

Phenotypic heterogeneity in Alzheimer's disease.

Probable heterogeneity of Alzheimer's disease is still debated. Many authors report heterogeneity on phenotypic and/or genetic level. We have tried to reveal if variability exists also in an Italian kindred (family N) with early onset Alzheimer's disease in which the illness has been transmitted in a mendelian autosomal fashion since the early eighteenth century. The only parameter that varies widely is the age at death of affected members and it was taken as an index of expression, a measure of phenotypic variability. Extension of this concept will be discussed.

Adult↗
PubMed2003

Genetic and phenotypic heterogeneity in patients with mandibuloacral dysplasia-associated lipodystrophy.

Mandibuloacral dysplasia (MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, and mottled cutaneous pigmentation. Patients with MAD develop two patterns of lipodystrophy: type A pattern, with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions; and type B pattern, with a more generalized loss of sc fat involving the face, trunk, and extremities. Recently, affected patients from five consanguineous Italian pedigrees with partial lipodystrophy (type A) were reported to have a homozygous R527H mutation in LMNA (lamin A/C) gene. We carried out mutational analysis of LMNA in affected patients from six pedigrees. Affected patients from two pedigrees with type A lipodystrophy had the homozygous R527H mutation in LMNA. The other four affected subjects who had type B lipodystrophy did not have any mutation in the exons and splice site junctions of LMNA; RNA extracted from lymphoblasts of two of these patients also revealed normal sequence. In these four subjects, sequencing of other known genes implicated in lipodystrophies, i.e. AGPAT2, Seipin, and PPARG also revealed no substantial alterations. We conclude that MAD is a genetically and phenotypically heterogeneous disorder. Besides LMNA gene, other as yet unmapped loci could be linked to MAD.

Adolescent↗
PubMed1997

Interfamilial and intrafamilial phenotypic heterogeneity in familial Alzheimer's disease.

The features of Alzheimer's disease (AD) are very heterogenous, and some component of the variability of AD is likely to be related to genetic factors. To investigate this question, we evaluated 19 clinical neuropsychiatric and brain imaging features in 32 familial Alzheimer's disease (FAD) kindred, primarily of late onset. Within families, patients displayed a high degree of phenotypic heterogeneity (PH), which occurred irrespective of gender, ethnicity, or apolipoprotein E genotype. Overall, an equivalent amount of PH was observed in both the between- (37%) and within-family (31%) groups. However, for onset age and rate of decline between families, there was greater PH than within families (P = .002 and P = .01, respectively). A similar trend was found for severity of cortical atrophy (P = .05). These observations suggest a weak genetic influence, and possibly strong nongenetic influences, on the degree of phenotypic heterogeneity in late-onset FAD. In early-onset AD kindred, a much smaller degree of phenotypic heterogeneity may be expected within families, because genetic influences in phenotypic expression tend to be more prominent in early-onset cases.

Aged↗
PubMed2006

Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium.

Mammalian endothelial cells (ECs) display marked phenotypic heterogeneity. Little is known about the evolutionary mechanisms underlying EC heterogeneity. The last common ancestor of hagfish and gnathostomes was also the last common ancestor of all extant vertebrates, which lived some time more than 500 million years ago. Features of ECs that are shared between hagfish and gnathostomes can be inferred to have already been present in this ancestral vertebrate. The goal of this study was to determine whether the hagfish endothelium displays phenotypic heterogeneity. Electron microscopy of the aorta, dermis, heart, and liver revealed ultrastructural heterogeneity of the endothelium. Immunofluorescent studies demonstrated marked differences in lectin binding between vascular beds. Intravital microscopy of the dermis revealed histamine-induced adhesion of leukocytes in capillaries and postcapillary venules, but no such adhesion in arterioles. Together, these data suggest that structural, molecular, and functional heterogeneity of the endothelium evolved as an early feature of this cell lineage.

Animals↗
PubMed1979

The use of multiple thresholds and segregation analysis in analyzing the phenotypic heterogeneity of multifactorial traits.

(1) Three models based on multifactorial inheritance are introduced to account for phenotypic heterogeneities. These models are used to determine whether subforms of a triat are: (a) different degrees of the same process, (b) non-familial environmental variants of the same process, and (c) independently transmitted processes. (2) The parameters of each model consist of two population prevalences and either one, two, or three correlation coefficients which reflect the three hypotheses given above. The models are formulated so that a likelihood ratio test may be performed to discriminate between them. (3) The following types of analyses are described: (a) analysis of prevalence data with separate population prevalence estimates, (b) analysis of prevalence data with the proband a parent with specified spouse, (c) analysis of prevalence data with the proband an offspring with specified parents, and (d) the full segregation distribution of families using Complex Segregation Analysis. (4) When compared with the Analysis of Prevalences, Complex Segregation Analysis has the following advantages: (a) the number of degrees of freedom for parameter estimates is greater and separate estimates of the population prevalences are not necessary, (b) standard errors of the parameters are smaller, and (c) the power to discriminate models is increased. (5) Phenotypic heterogeneities such as age of onset, severity, and sex effect can be more completely understood by the methods of analyses described above. The nosology of familial disorders can also be clarified, and environments relevant to the transmission of the trait can be detected. This approach is particularly suitable for the analysis for behavioural traits since it does not require the assumption that environmental effects common to relatives be ignored. (6) Finally, our experience indicates that incorporating both prevalence and pedigree data into a single analysis decreases the time required to perform the analysis.

Environment↗
PubMedDate not supplied

Molecular basis for phenotypic heterogeneity in galactosaemia: prediction of clinical phenotype from genotype in Japanese patients.

We identified 14 mutations in 15 Japanese subjects from 13 families with galactose-1-phosphate uridyltransferase (GALT) deficiency using denaturing gradient gel electrophoresis (DGGE) and direct sequence analysis. These mutations accounted for 22 (96%) of 23 mutant alleles in 15 Japanese subjects. The mutational spectrum included nine missense mutations (M142V, G179D, A199T, R231H, W249R, N314D, P325L, R333Q, and R333W), two deletions (L275fsdelT and Q317fsdelC), a nonsense mutation (W249X), and two splicing mutations (V85-N97fsdel38bp and IVS4nt+1). Ten of the 14 mutations have not been reported in Caucasians. Differences in frequency and spectrum of GALT mutations suggest that the mutations may have occurred after racial divergence of Caucasians and Asians. The Duarte variant in Japanese was associated with the N314D mutation, g.1105G > C, g.1323G > A, and g.1391G > A (SacI -) polymorphisms, as in Caucasians. The Duarte variant may have occurred before racial divergence, and was an ancient mutation. In vitro GALT activities of nine missense mutations were determined by a COS cell expression system, and indicated between 1.3% and 35% of wild-type control. Patients with R333Q (29% in vitro GALT activity) or A199T (35%) showed mild clinical phenotypes, i.e. no ovarian failure or neurological deterioration. Genotype determination is useful for predicting biochemical and clinical phenotypes in classic galactosaemia, and can be of further help in managing patients with this disorder.

Adolescent↗
PubMed1989

Phenotypic heterogeneity studied by immunohistochemistry and aneuploidy in non-small cell lung cancers.

Non-small cell lung cancers (non-SCLC) differ from small cell lung cancers (SCLC) by many clinical features and prognosis. However, recent studies suggest that lung cancer heterogeneity frequently leads to the association of SCLC and non-SCLC in the same tumor. This phenotypic heterogeneity can be analyzed by immunohistochemistry using monoclonal antibodies (Mab) raised against differentiation related antigens. It may have clinical relevance inasmuch as the diversification of malignant cells is a well-known factor of tumor progression and may be due to chromosomal instability because inappropriate gene expression leads to the formation of antigens unrelated to cell lineage. Chromosomal instability in cancer leads to aneuploidy detectable by cell DNA content analysis. In a prospective study, we analyzed, in parallel, the expression of neuroendocrine related antigens by immunohistochemistry and the cell DNA content in frozen specimens from 40 patients who underwent complete surgical resection of primary non-SCLC in an attempt (a) to characterize the phenotypic heterogeneity and (b) to determine whether this heterogeneity is correlated with aneuploidy and clinical staging. Three Mabs were used in association as a marker of neuroendocrine antigen expression (S-L 11.14, MOC-1, and NE-25); reactivity of these Mabs in 9 SCLC and 3 lung carcinoid tissue sections was used as positive control. All SCLC and 2 of 3 lung carcinoids tested were homogeneously positive with Mabs S-L 11.14, MOC-1, and NE-25; 13 of 40 non-SCLC were homogeneously positive and 11 additional specimens focally positive with Mabs S-L 11.14, MOC-1, and NE-25. The frequency of this abnormal phenotype was significantly higher in poorly differentiated squamous cell carcinomas (chi 2 10.08; P less than 0.005), in clinical stage III non-SCLC (chi 2 5.93; P less than 0.02), and in tumors involving mediastinal lymph nodes (chi 2 5; P less than 0.03). The percentage of cells in the modal DNA of G0-G1 phase was significantly lower in non-SCLC homogeneously positive with Mabs S-L 11.14, MOC-1, and NE-25 [27.4 +/- 10.3% (SD)] in comparison with non-SCLC negative with these same Mabs [56.8 +/- 21.3%; P less than 0.01, Mann-Whitney U test]. We conclude that (a) mixed SCLC-non-SCLC differentiation is frequent and can be assessed by immunohistochemistry, (b) neuroendocrine differentiation in non-SCLC is mainly observed in poorly differentiated tumors and in advanced clinical stages, and that (c) this heterotopic phenotype is correlated with aneuploidy and has clinical implications.

Adult↗
PubMed2001

Accumulation, distribution and phenotype heterogeneity of mast cells (MC) in human brains with neurocysticercosis.

Neurocysticercosis (NCC) is one of the most common parasitic brain infections in the world NCC can cause widely varied clinical manifestations, mainly due to the host immune-inflammatory response. The immunological hallmark of the infection with helminth parasites is infiltration into the inflamed mucosa of the gastrointestinal tract of numerous mast cells. It has been postulated that mediators released by activated mast cells might contribute to the local inflammatory response. Since data concerning the association of mast cells with neurocysticercosis are not available, the aim of our study is to determine the distribution and phenotypes of mast cells in human brain infested by cysticerci. The study was performed on 20 human autopsy brains. Mast cells (MC) were identified by means of immunohistochemical method using specific MC tryptase and chymase monoclonal antibodies. In the control brains, mast cells were very few and showed a very sparse distribution. They had been occasionally found in meninges and in perivascular areas of some brain blood vessels. Those cells were mainly tryptase-chymase phenotype (MCTTC). In contrast, in the brain sections with neurocysticercosis, mast cells were numerous. A striking feature of identified mast cells was their phenotype heterogeneity. The tryptase mast cells (MCT) phenotype dominated over the tryptase-chymase (MCTC) phenotype. MCT infiltrated mainly meninges and brain parenchyma around cysts with viable and necrotic parasites. MCTC infiltrated perivascular area of the blood vessels penetrating to the depth of the brain. Summarising, this is the first report which documents the accumulation and phenotype heterogeneity of mast cells in human brains with neurocysticercosis. Our findings suggest that the effector mechanism responsible for the host responses to the parasitic infection that involves numerous mast cells in the human brain may be very important for pathomechanism of this disease.

Adolescent↗
PubMed1988

Phenotypic heterogeneity and cytotoxic activity of Con A and IL-2-stimulated cultures of mouse Thy-1+ epidermal cells.

Short-term and long-term cultures of mouse Thy-1+ epidermal cells (EC) were established in order to characterize their phenotypic and functional properties. Concanavalin A (Con A) and Interleukin 2 (IL-2) stimulated Thy-1+ EC mediated non-MHC directed cytotoxicity preferentially against the NK-sensitive target, YAC-1 vs the NK-resistant target, P815; these cells also mediated antibody-dependent cell-mediated cytotoxicity (ADCC), indicating the presence of IgG-FcR on at least some of them. Freshly isolated Thy-1+ EC failed to lyse YAC-1 targets; however, this activity was observed after 9 d of culture with Con A and IL-2. While dendritic Thy-1+ EC, in vivo, do not express the T-cell markers, L3T4 and Lyt-2, short-term cultured cells displayed phenotypic heterogeneity with small but significant percentages of Lyt-2+ and L3T4+ cells appearing transiently. The phenotype of the effector cell(s), which mediates cytotoxic activity, was determined by utilizing flow cytometry to sort short-term cultured EC into positively and negatively stained populations. Cells which express L3T4, or which lack asialo GM1, did not lyse YAC-1 targets; maximum cytotoxic activity was found within populations of cells which are asialo GM1+, Lyt-2-, and asialo GM1+, Lyt-2+. These studies indicate that Thy-1+ cells derived from mouse epidermis when cultured in the presence of Con A and IL-2 have the capacity to generate a phenotypically heterogeneous population, some cells of which are capable of mediating cytotoxic activities.

Animals↗
PubMed1989

Metastatic human melanoma. Phenotypic heterogeneity and antigen expression in relation to the clinical status.

According to animal experiments, metastasis to a particular organ depends on the phenotype of the tumor cells. Widespread metastatic dissemination including internal organs would therefore, at least in part, depend on the capacity of tumor cells to modulate, resulting in increased phenotypic heterogeneity. We found evidence for this assumption in human melanoma by phenotyping metastases (mainly cutaneous/subcutaneous) from 59 patients by the use of six monoclonal antibodies. Interlesional antigenic heterogeneity was present in 22/33 (67%) patients with disseminated metastases including at least one internal organ, but only in 4/26 (15%) patients whose metastases were restricted to skin and/or skin-draining lymph nodes (P less than or equal to 0.01). Chemotherapy cannot be the main reason for interlesional phenotypic heterogeneity, as seen by comparison of treated and untreated patients. Aneuploid melanoma metastases, as an indication for instability on the chromosomal level, were found in the majority of patients (84%) regardless of their clinical situation. Widespread disease was significantly related to the loss of the cytoplasmatic antigen K-1-2 and to the expression of the 130-kDa membrane antigen A-1-43.

Antigens, Neoplasm↗
PubMed1988

The intraclonal and interclonal phenotypic heterogeneity in a rhabdomyosarcoma cell line with abortive imitation of embryonic myogenesis.

Three distinct subpopulations (A, B, C) derived from a dimethylbenzanthracene-induced rat rhabdomyosarcoma were established as permanent cell lines. Although the clonal nature of each of these subpopulations was confirmed by repeated recloning procedures, a striking intraclonal phenotypic heterogeneity was observed. By means of immunofluorescence microscopy and transmission electron microscopy, it could be shown that these subpopulations closely recapitulate stages of embryonic rhabdomyogenesis both in vitro and in vivo, but differ in their particular range of maximum differentiation. Embryonic rhabdomyogenesis is imitated most perfectly by subpopulation C, in which multinuclear myotubes are formed in vitro by fusion of mononuclear cells, and alpha-sarcomeric actin is expressed in the multinuclear cells and in a few mononuclear cells. After retransplantation in vivo, subpopulation C further proceeds in fine structural differentiation, now exhibiting myofibrils with a sarcomeric organization in the myotube-like giant cells. The cells of subpopulation B do not exceed the stage of mononuclear desmin-positive cells in vitro, but synthesize thin and thick myofilaments after retransplantation in vivo. The cells of subpopulation A recapitulate embryonic rhabdomyogenesis least successfully being confined to the stage of mononuclear desmin-positive cells. Thus, the coexistence of diverse subpopulations and the cellular maturation within these subpopulations together contribute to the phenotypic heterogeneity of rhabdomyosarcomas.

Animals↗