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Results for “Phenotypic variability”

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PubMed2001

Accuracy of two-dimensional electrophoresis for target discovery in human colorectal cancer.

Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) is increasingly used for target discovery in human disease to complement genomic studies. We have assessed the possibilities and limits of 2-D PAGE applied to human colorectal cancer. Up to 10(8) epithelial cells were purified from paired normal and pathological biopsies using Ber-EP4 coated magnetic beads, allowing the elimination of cellular and fluid contaminations. The mean coefficient of variation (CVAR) of repeated 2-D PAGE analysis with silver staining was lying between 20 and 28%. However, only 47% (interrun) to 76% (intrarun) of spots could be matched within a triplicate experiment. Interindividual phenotypic variability was high. Intratumoral phenotypic variability was not found to be significant. When method and tumor variability were added, 90% of CVAR were inferior to 48%. Thus, two-fold up- or down-regulation of protein expression reveals biological significance. Serial paired comparison of 923 proteins in 10 patients showed highly reproducible differences between normal and cancer tissues. Under well defined experimental conditions and after the high variability of the technique has been considered, 2-D PAGE parallel analysis of paired colorectal samples allows patient-specific tumor profiling.

Colorectal Neoplasms↗

PubMed1999

HESX1: a novel gene implicated in a familial form of septo-optic dysplasia.

The homeobox gene Hesx1, which encodes a pituitary transcription factor, is first expressed at gastrulation in the mouse embryo. Hesx1 expression begins in prospective forebrain tissue but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Transgenic mice lacking Hesx1 exhibit a phenotype comprising variable anterior CNS defects, such as a reduced prosencephalon, abnormalities in the corpus callosum and septum pellucidum, anophthalmia or microphthalmia, defective olfactory development and bifurcations in Rathke's pouch with pituitary dysplasia. A comparable and highly variable phenotype in humans is septo-optic dysplasia. We have cloned and sequenced the human homologue HESX1 and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis. Two siblings with septo-optic dysplasia were homozygous for a missense mutation within the HESX1 homeobox. This mutation resulted in the substitution of a highly conserved arginine residue (Arg53) by cysteine and led to a loss of in vitro DNA binding. Hence, a vital role for Hesx1/HESX1 in forebrain and pituitary development in mice and humans is suggested.

Animals↗

PubMed1991

Evidence that a single gene with gender- and age-dependent effects influences systolic blood pressure determination in a population-based sample.

A biometrical study was carried out to evaluate the role of genetic variation in determining interindividual differences in systolic blood pressure (SBP) in the population at large. SBP was measured in 1,266 Caucasian individuals in 278 pedigrees ascertained through children enrolled in the Rochester, MN, school system. The sample included 646 males and 620 females 550 years of age and not taking antihypertensive medication or oral contraceptives. Complex segregation analysis was first applied to these data by using a regression model for age, in which the intercept was gender and ousiotype specific but in which the slope was only gender specific. When the slope was independent of ousiotype, neither variation at a single gene combined with polygenic effects (mixed genetic model) nor variation in a single environmental factor combined with polygenetic effects (mixed environmental model) explained the distribution of SBP in this sample. However, when the regression model for age allowed both the intercept and slope to be gender and ousiotype specific, the mixed environmental model was rejected whereas the mixed genetic model was not. These results suggest that variability in SBP may be influenced by major effects of allelic variation at a single gene that are both gender and age dependent. This study (1) suggests that particular genotypes determined by a single gene are associated with a steeper increase of SBP with age among males and females 550 years of age in the general population and (2) illustrates the need to consider models that more realistically represent the relationship between genotypic variability and phenotypic variability, to understand the genetics of human quantitative traits.

Adolescent↗

PubMed1999

Mapping of post-flowering drought resistance traits in grain sorghum: association between QTLs influencing premature senescence and maturity.

The identification of genetic factors underlying the complex responses of plants to drought stress provides a solid basis for improving drought resistance. The staygreen character in sorghum (Sorghum bicolor L. Moench) is a post-flowering drought resistance trait, which makes plants resistant to premature senescence under drought stress during the grainfilling stage. The objective of this study was to identify quantitative trait loci (QTLs) that control premature senescence and maturity traits, and to investigate their association under post-flowering drought stress in grain sorghum. A genetic linkage map was developed using a set of recombinant inbred lines (RILs) obtained from the cross B35 x Tx430, which were scored for 142 restriction fragment length polymorphism (RFLP) markers. The RILs and their parental lines were evaluated for post-flowering drought resistance and maturity in four environments. Simple interval mapping identified seven stay-green QTLs and two maturity QTLs. Three major stay-green QTLs (SGA, SGD and SGG) contributed to 42% of the phenotypic variability (LOD 9.0) and four minor QTLs (SGB, SGI. 1, SGI.2, and SGJ) significantly contributed to an additional 25% of the phenotypic variability in stay-green ratings. One maturity QTL (DFB) alone contributed to 40% of the phenotypic variability (LOD 10.0), while the second QTL (DFG) significantly contributed to an additional 17% of the phenotypic variability (LOD 4.9). Composite interval mapping confirmed the above results with an additional analysis of the QTL x Environment interaction. With heritability estimates of 0.72 for stay-green and 0.90 for maturity, the identified QTLs explained about 90% and 63% of genetic variability for stay-green and maturity traits, respectively. Although stay-green ratings were significantly correlated (r = 0.22, P< or =0.05) with maturity, six of the seven stay-green QTLs were independent of the QTLs influencing maturity. Similarly, one maturity QTL (DFB) was independent of the staygreen QTLs. One stay-green QTL (SGG), however, mapped in the vicinity of a maturity QTL (DFG), and all markers in the vicinity of the independent maturity QTL (DFB) were significantly (P< or =0.1) correlated with stay-green ratings, confounding the phenotyping of stay-green. The molecular genetic analysis of the QTLs influencing stay-green and maturity, together with the association between these two inversely related traits, provides a basis for further study of the underlying physiological mechanisms and demonstrates the possibility of improving drought resistance in plants by pyramiding the favorable QTLs.

Agriculture↗

PubMed2005

Skewed X inactivation of the normal allele in fully mutated female carriers determines the levels of FMRP in blood and the fragile X phenotype.

BACKGROUND: The variable phenotype in female carriers of a full mutation is explained in part by non-random X-chromosome inactivation. The molecular diagnosis of fragile X syndrome is based on the resolution of the number of CGG triplet repeats and the methylation status of a critical CpG in the fragile X mental retardation gene (FMR1) promoter. Neighboring CpGs in the FMR1 promoter are supposed to be equally methylated or unmethylated. METHOD: Southern blot analysis was performed with double digestion, either with EcoRI/EagI or with HindIII/SacII. The EagI restriction site was studied by sequencing. The fragile X encoded protein (FMRP) was detected in white blood cells by Western blot. The fragile X phenotype was evaluated by specific clinical examinations. RESULTS: Within one family we found three female carriers of a full mutation and a different degree of methylation of the normal allele that correlated with the levels of FMRP in blood and the fragile X phenotype. Complete methylation at the EagI CpG target (but partially methylated SacII CpG site) was associated with extremely skewed X inactivation (confirmed by analysis of the methylation status at the PGK locus), undetectable FMRP in blood, and a male-like phenotype. CONCLUSIONS: In fully mutated female carriers the methylation status at the EagI restriction site correlates with the levels of FMRP in blood and the fragile X phenotype. Neighboring CpG sequences in the FMR1 promoter can be differentially methylated, which should be taken into consideration for molecular diagnosis.

Alleles↗

PubMed2005

A novel 9 bp deletion in the filamin a gene causes an otopalatodigital-spectrum disorder with a variable, intermediate phenotype.

We report a four-generation pedigree with six affected females with cranial hyperostosis and various skeletal abnormalities. The phenotype is similar to frontometaphyseal dysplasia, which is part of the otopalatodigital (OPD) spectrum. We identified a novel in-frame deletion in exon 29 of the Filamin A gene (c.4904_4912del, p.R1635_V1637del) encoding rod domain repeat 14 of the protein. The disorder resulted in early lethality in male children. The phenotype of female individuals in this family is variable and rather mild, and bridges the phenotypes of various OPD-spectrum disorders.

Base Sequence↗

PubMed2001

The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome.

A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur.

Adult↗

PubMed2001

Statistical aspects of quantitative image analysis of beta-amyloid in the APP(V717F) transgenic mouse model of Alzheimer's disease.

Cerebral beta-amyloidosis is a central part of the neuropathology of Alzheimer's disease (AD). Quantitation of beta-amyloid plaques in the human AD brain, and in animal models of AD, is an important study endpoint in AD research. Methodologic approaches to the measurement of beta-amyloid in the brain vary between investigators, and these differences affect outcome measures. Here, one quantitative approach to the measurement of beta-amyloid plaques in brain sections was analyzed for sources of variability due to sampling. Brain tissue was from homozygous APP(V717F) transgenic male mice. Sampling variables were at the mouse and microscopic slide and field levels. Results indicated that phenotypic variability in the mouse sample population was the largest contributor to the standard error of the analyses. Within each mouse, variability between slides or between fields within slides had smaller effects on the error of the analyses. Therefore, when designing studies of adequate power, in this and in other similar models of cerebral beta-amyloidosis, sufficient numbers of mice per group must be included in order for change in mean plaque burden attributable to an experimental variable to outweigh phenotypic variability.

Alzheimer Disease↗

PubMed2001

Pena-Shokeir phenotype with variable onset in three consecutive pregnancies.

The Pena-Shokeir phenotype represents an autosomal recessive syndrome characterized by neurogenic arthrogryposis, facial anomalies and pulmonary hypoplasia. Prenatal diagnosis of this disease has been reported prospectively and in cases with positive family history. We describe here a patient who has had three consecutive pregnancies affected by the Pena-Shokeir syndrome. In these pregnancies, the onset of the arthrogryposis varied between the 12th and the 18th week of gestation. Therefore, the possibility of a variable chronological development of the main diagnostic feature of the syndrome, arthrogryposis, has to be taken into proper consideration while counseling families with a positive history for the Pena-Shokeir phenotype.

Adult↗

PubMed2005

What can cell biology tell us about heterogeneity in lysosomal storage diseases?

UNLABELLED: Lysosomal storage diseases are clinically heterogeneous with respect to their age of onset, progression of symptoms and the particular organs involved. Varying levels of residual enzyme activity, associated with different defective alleles that cause the respective diseases, are responsible in part for this clinical heterogeneity. In general, the higher the residual enzyme activity, the milder the phenotype. Enzyme activity in severe forms of disease is frequently zero, and in mild forms usually does not exceed approximately 5%. However, the correlation is not so strict as to allow prediction of the phenotype of individual patients. The molecular basis of the different levels of enzyme activity can only be revealed by biochemical investigations of the defective lysosomal proteins. Null alleles may be due to splice-site mutations or deletions. In the case of missense mutations, enzymes frequently fold incorrectly and are retained in the endoplasmic reticulum and subsequently degraded. As these enzymes do not reach the lysosome, they do not provide any functional residual activity. Residual enzyme activity is only observed in cases where the defective enzyme reaches the lysosome and has retained enzymatic activity. Patients carrying the same mutant alleles still show considerable phenotypic variability due to modifying genes and epigenetic factors. None of these has so far been elucidated. However, there are some indications that differences in splicing-factor machinery may influence the phenotypic expression of splice-site mutations and that hormonal modulation of secondary microglial activation in lipidosis may also influence the disease course. CONCLUSION: Phenotypic variability is a frequent phenomenon in lysosomal storage diseases. Residual enzyme activity has been identified as one of the factors influencing the clinical outcome of disease; however, it is obvious that other genetic and epigenetic factors also affect phenotypic variability, particularly in patients with late onset disease.

Alleles↗

PubMed2005

Influence of growth environment on tolerance to UV-B radiation, germination speed, and morphology of Metarhizium anisopliae var. acridum conidia.

We previously reported wide variability in UV-B tolerance among different Metarhizium anisopliae isolates [Braga, G.U.L., Flint, S.D., Miller, C.D., Anderson, A.J., Roberts, D.W., 2001a. Variability in response to UV-B among species and strains of Metarhizium isolated from sites at latitudes from 61 degrees N to 54 degrees S. J. Invertebr. Pathol. 78, 98-108] as well as wide phenotypic variability in some of these isolates in response to alterations in their growth environments [Rangel, D.E.N., Braga, G.U.L., Flint, S.D., Anderson, A.J., Roberts, D.W., 2004. Variations in UV-B tolerance and germination speed of M. anisopliae conidia produced on artificial and natural substrates. J. Invertebr. Pathol. 87, 77-83]. Studies on other biological systems have demonstrated that strong selective pressure for tolerance to a stress factor may reduce the phenotypic variability of this trait. In the present study, conidia of the isolate most tolerant to radiation and heat, ARSEF 324, presented very little phenotypic variability in UV-B tolerance in response to production on either artificial culture medium or infected insects. The phenotypic plasticities in two other traits (conidial morphology and germination speed), however, were considerably higher.

Animals↗

PubMed2006

Phenotypic approaches for understanding patterns of intracemetery biological variation.

This paper reviews studies of phenotypic inheritance and microevolutionary processes in archaeological populations using data on cranial and dental phenotypic variation, often referred to as paleogenetics or biodistance analysis. The estimation of biological distances between populations, or among individuals within populations, is one component of bioarchaeological research on past populations. In this overview, five approaches that focus on morphological variation within cemeteries are summarized: kinship and cemetery structure analysis, postmarital residence analysis, sample aggregate phenotypic variability, temporal microchronology, and age-structured phenotypic variation. Previous research, theoretical justifications, and methods are outlined for each topic. Case studies are presented that illustrate these theoretical and methodological bases, as well as demonstrate the kinds of inferences possible using these approaches. Kinship and cemetery structure analysis seeks to identify the members of family groups within larger cemeteries or determine whether cemeteries were kin-structured. Analysis of sex-specific phenotypic variation allows estimation of postmarital residence practices, which is important for understanding other aspects of prehistoric social organization. Analysis of aggregate phenotypic variability can be used to infer site formation processes or cemetery catchment area. The study of temporal microchronologies can be used to evaluate provisional archaeological chronologies or study microevolutionary processes such as adaptive selection or changing patterns of gene flow. Finally, age-structured phenotypic variation can be reflective of selection processes within populations or it can be used as a measure of morbidity, growth arrest, and early mortality within past populations. Use of phenotypic data as a genotypic proxy is theoretically sound, even at small scales of analysis.

Adolescent↗

PubMed1995

The search for genetic mechanisms of congenital heart disease.

Identification of the genetic basis for congenital heart defects has been a topic of inquiry for pediatric cardiologists for many years. Any genetic model proposed must account for three often puzzling features of congenital heart diseases, namely the high population incidence, the less than Mendelian recurrence risk, and low concordance rates of heart lesions within individual families. A multifactorial or polygenic inheritance model has been used to explain these observations. Although this model has been serviceable, it does not adequately explain the phenotypic variability within families. Further, the emphasis on teratogenic influences has not led to the elucidation of pathogenetic mechanisms. The multifactorial model should be modified to include the role of chance as originally proposed by Kurnit. Once the role of chance is acknowledged, the phenotypic variability of congenital heart diseases becomes less problematic, and the multifactorial model gives way to a model in which single genes are capable of producing congenital heart disease. Through recent work in animal models and humans, it is now clear that single congenital heart disease genes can be identified that produce phenotypic variability in families that is similar to that seen in the population as a whole. Examples demonstrating recent progress in the search for major congenital heart disease genes are discussed.

Animals↗

PubMed1998

A variable monilethrix phenotype associated with a novel mutation, Glu402Lys, in the helix termination motif of the type II hair keratin hHb1.

Monilethrix is a rare human hair disorder with autosomal dominant transmission that can be caused by mutations in hair keratins. Up until now, pathogenic mutations in the type II hair cortex keratins hHb6 and hHb1 were restricted to a highly conserved glutamic acid residue Glu413 (Glu117 of the 2B subdomains) in the EIATYRRLLEGEE helix termination motif of the two keratins. The critical glutamic acid residue was substituted either by a lysine or, less frequently, by an aspartic acid residue. Here we report a novel mutation in a French monilethrix family, which again consists of a lysine substitution of another highly conserved glutamic acid residue, Glu402 (Glu106 of the 2B subdomain), in the EIATYRRLLEGEE motif of hHb1. Family members bearing the hHb1 Glu402Lys mutation exhibit a particularly variable disease phenotype. The pedigree comprises two infant members, one with pronounced dystrophic alopecia, follicular keratosis, and clear-cut moniliform hair, and one with no hair loss at all and moniliform hair detectable only by electron microscopy, as well as an adult individual without any clinically or electron microscopically detectable symptoms, but with clear historical proof of the disease.

Adult↗

PubMed2003

Skin expression of metalloproteinases and tissue inhibitor of metalloproteinases in sibling patients with recessive dystrophic epidermolysis and intrafamilial phenotypic variation.

A number of COL7A1 mutations have now been reported in recessive dystrophic epidermolysis bullosa patients, and the analysis of phenotype-genotype correlations showed evidence for interfamilial and intrafamilial phenotypic variability, occurring for the same mutation. Collagenase and stromelysin activities have been found to be overexpressed in skin cultures of some recessive dystrophic epidermolysis bullosa patients, and tissue destruction in the disease process might result from an imbalance of metalloproteinases (MMP) over tissueinhibitor of metalloproteinases (TIMP). So we suspected that the phenotypic variability for the same mutation could be linked to other genetic or environmental factors, as a particular balance between MMP and TIMP. Organ cultures were performed using explants from the skin of three patients from the same family with recessive dystrophic epidermolysis bullosa to reveal and quantify the expression of MMP-1 (collagenase 1), MMP-2 and MMP-9 (gelatinases A and B), MMP-3 (stromelysin 1), TIMP-1, and TIMP-2, and to compare the results with those obtained with two human control skins, with the same experimental conditions. Increased amounts of all metalloproteinases investigated were observed in the skin of the three recessive dystrophic epidermolysis bullosa affected sibling brothers, both in lesioned and in apparently nonlesioned skin, compared with controls. The amounts of MMP-1, MMP-2, MMP-3, and MMP-9 increased particularly in the skin of the more clinically affected patient. Furthermore for this patient we evidenced higher amounts of MMP-1 and also a lower TIMP-1 amount in his unlesioned and lesioned skin compared with the other two affected patients and with healthy control donors. So we can suspect that recessive dystrophic epidermolysis bullosa phenotypic variability could be related to patients' collagenase activity heterogeneity, linked to imbalance between MMP-1 and TIMP-1.

Adolescent↗

PubMedDate not supplied

[Variability and phenotypic structure of Proteocephalus torulosus (Cestoda: Proteocephalidea)--a parasite of cyprinid fishes].

Variability of 5 qualitative features of Proteocephalus torulosus from 6 fish species belonging to 5 genera of the subfamily Leuciscinae was studied. Itraspecific diversity is represented by 3 scolex forms, 2 types of proglottid structure, 3 proglottid shapes, and 2 variations of the female reproductive system characteristics. The parasite living in different host species form separate ecological forms differing in the number of phenotypes and their ratio. However, the same scolex and strobila phenotypes dominate in the range of the parasite. Two P. torulosus groupings have been recognised the European and Asian ones, which differ in the representation of the proglottid structure types.

Animals↗

PubMed1983

Ring chromosome 6: variability in phenotypic expression.

We present four children with a ring chromosome 6. Clinically, these cases are quite variable. A review of ten previously reported cases also suggests difficulty of phenotype-karyotype correlation in patients with a ring 6.

Adult↗

PubMed2005

Modifier genes play a significant role in the phenotypic expression of PKD1.

BACKGROUND: Polycystic kidney disease type 1 (PKD1) is characterized by extreme variation in the severity and progression of renal and extrarenal phenotypes. There are significant familial phenotype differences; but it is not clear if this is due to differences in PKD1 mutations, differences in genetic background, or both. METHODS: A total of 315 affected relatives (83 PKD1 families) without end-stage renal disease (ESRD) were evaluated for disease markers, including renal volume, creatinine clearance, proteinuria, liver cysts, and hypertension. Of these patients, 19% progressed to ESRD within 1 to 10 years after the initial examination. Nested analysis of variance was used to investigate interfamilial and intrafamilial differences in these phenotypes. Heritability analyses were used to estimate the effect of the genetic background on phenotypic variability. The age of onset of ESRD was also analyzed with an additional 389 family members from the same PKD1 families without clinical evaluation but with data on age of onset of ESRD (or age without ESRD). RESULTS: There were significant phenotype differences between patients with the same mutation and different genetic backgrounds. The phenotypic variation between patients with different mutations and different genetic backgrounds was not significantly greater than the variation between patients with the same mutation and different genetic backgrounds. However, when the 389 family members were included, both the mutation and modifier genes had significant effects on the age of onset of ESRD. Inherited differences in genetic background were estimated to account for 18% to 59% of the phenotypic variability in PKD1 disease markers in patients prior to ESRD and in the subsequent progression to ESRD (43% heritability) in the 315 patients who were clinically evaluated. CONCLUSION: Modifier loci in the genetic background are important factors in inter- and intrafamilial variability in the phenotypic expression of PKD1. The extreme intrafamilial phenotype differences are consistent with the hypothesis that one or a few modifier genes have a major effect on the progression and severity of PKD1.

Adult↗