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PubMed2002

Invasive depth of extravillous trophoblast correlates with cellular phenotype: a comparison of intra- and extrauterine implantation sites.

During intrauterine human placentation, extravillous trophoblast invades uterine tissues starting with proliferating stem cells at the basement membrane of anchoring villi. Transition to the postproliferative invasive phenotype takes place several cell layers distant. Here we show that in intrauterine pregnancies invasive trophoblast comprises three cellular phenotypes: a. Small spindle-shaped trophoblast cells are found along the whole invasive pathway throughout pregnancy. They are embedded in little heterogeneous extracellular matrix but expose only fibronectin receptors (integrins alpha5beta1, alphavbeta3/5), resulting in a partial integrin-matrix mismatch. b. Large polygonal trophoblast cells are rare in early pregnancy but increase in number towards term. They secrete ample heterogeneous extracellular matrix and expose integrins specifically matching the opposing matrix molecules (integrins alpha6beta4, alpha5beta1). c. Multinucleated giant cells in all stages of pregnancy form a kind of peripheral shell of trophoblast. In contrast to intrauterine pregnancies, in viable tubal pregnancies, Mib-1 expression indicating proliferation, extends deeply into the invasive pathway. Trophoblast cells of the invasive pathway mostly belong to the small spindle-shaped phenotype and secrete little extracellular matrix, mainly fibronectins. At the transition to the second cellular layer of cell columns expression of integrin alpha6beta4 switches to expression of alpha5beta1 and alphavbeta3/5. Viable tubal pregnancies are characterised by a broad overlap of proliferative with invasive phenotype as well as a general integrin-matrix mismatch. The differences in proliferation patterns, cellular phenotype and matrix-integrin co-localisation may well explain the increase of invasiveness of normal extravillous trophoblast from term intrauterine via early intrauterine to viable tubal pregnancies.

Cell Count↗

PubMed2026

Comparative Genome-Wide Association Studies of Metabolites and Grain-Related Traits in Common Wheat.

The metabolome is highly diverse and the closest layer to phenotype; therefore, it is commonly regarded as a bridge between the genome and phenome in plants. Here, we performed large-scale metabolome analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and 33 grain-related traits in a diverse panel of natural accessions and a recombinant inbred line (RIL) population. We identified a new network of 2286 associations between 947 metabolites and 33 grain-related traits. Systematic integration of metabolic genome-wide association study (mGWAS) and metabolic quantitative trait locus (mQTL) analyses identified 33 566 significant single-nucleotide polymorphisms (SNPs) and 3128 mQTL. Thirteen annotated metabolites co-localized within a physical interval on 7A. Integration of metabolite-based and phenotype-based GWAS and QTL revealed an overlapped region for gibberellin A4 (GA4) content and grain roundness on 4A. Phenotyping of an ethyl methanesulfonate (EMS)-induced mutant confirmed the role of TaSDR in regulating GA4 content and grain morphology. These findings provide novel insights into the metabolic pathways influencing key grain-related traits and advance our understanding of the complex molecular mechanisms regulating grain metabolites and phenotypes in wheat. The identified metabolic markers and candidate genes provide valuable targets for molecular breeding programs aimed at improving wheat yield and quality.

QTL↗

PubMed2000

The isolation and characterization in yeast of a gene for Arabidopsis S-adenosylmethionine:phospho-ethanolamine N-methyltransferase.

Saccharomyces cerevisiae opi3 mutant strains do not have the phospholipid N-methyltransferase that catalyzes the two terminal methylations in the phosphatidylcholine (PC) biosynthetic pathway. This results in a build up of the intermediate phosphatidylmonomethylethanolamine, causing a temperature-sensitive growth phenotype. An Arabidopsis cDNA library was used to isolate three overlapping plasmids that complemented the temperature-sensitive phenotype. Phospholipid analysis showed that the presence of the cloned cDNA caused a 65-fold reduction in the level of phosphatidylmonomethylethanolamine and a significant, though not equivalent, increase in the production of PC. Sequence analysis established that the cDNA was not homologous to OPI3 or to CHO2, the only other yeast phospholipid N-methyltransferase, but was similar to several other classes of methyltransferases. S-adenosyl-Met:phospho-base N-methyltransferase assays revealed that the cDNA catalyzed the three sequential methylations of phospho-ethanolamine to form phospho-choline. Phospho-choline is converted to PC by the CDP-choline pathway, explaining the phenotype conferred upon the yeast mutant strain by the cDNA. In accordance with this the gene has been named AtNMT1. The identification of this enzyme and the failure to isolate a plant phospholipid N-methyltransferase suggests that there are fundamental differences between the pathways utilized by yeast and by some plants for synthesis of PC.

Amino Acid Sequence↗

PubMed2004

Gene flow across a climatic barrier between hybridizing avian species, California and Gambel's quail (Callipepla californica and C. gambelii).

Allopatric species commonly interbreed in a restricted margin between their ranges. The particular factors that permit interbreeding between species determine the extent of hybridization and its significance for evolution and conservation. Using California quail and Gambel's quail (Callipepla californica and C. gambelii) that naturally hybridize in a narrow region between relatively mesic and xeric environments, I assessed the exchange of genetic and phenotypic traits in relation to vegetative and climatic features (temperature and precipitation) that characterize the area of range overlap, and I examined genetic and phenotypic traits within the hybrid zone over a five-year period in relation to variation in precipitation. Using microsatellite markers, this study reveals that genetic, plumage, and morphometric traits are tightly associated with vegetation, rainfall, and temperature profiles through the abrupt transition from one parental species to the other across the hybrid zone. Results show that the hybrid zone has remained clinal, stationary, and bounded over the five-year study period. There was no evidence of introgression outside the narrow hybrid zone. Interannual climatic fluctuations are associated with internal hybrid zone dynamics but did not alter the shape and position of the zone. A transect through the hybrid zone revealed rapid and episodic genetic mixing within the zone. Possible long-term consequences of this restricted hybridization for the evolution of the two parental species are discussed in the light of changing environments.

Animals↗

PubMed1999

Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN.

Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two hamartoma syndromes with distinct phenotypic features. Although partial clinical overlap exists between CS and BZS, they are considered to be separate entities. PTEN has been identified as the susceptibility gene for both disorders, suggesting allelism. We have identified a germline mutation, R335X, in PTEN in a family consisting of two female members with the phenotypic findings of CS and two male members with the phenotypic findings of BZS. To our knowledge, this is the first report that shows the presence of separate subjects with CS and with BZS in a single family associated with a single germline PTEN mutation.

Adult↗

PubMed1978

Use of a programmable calculator in processing and interpreting serum cholinesterase phenotypes.

Cholinesterase phenotyping is done at 25 degrees C with use of benzoylcholine as substrate and dibucaine, fluoride, chloride, and succinyldicholine as inhibitors. We wrote a diagnostic program in modified BASIC language for the processing and interpretation of these cholinesterase phenotypes. We used the HP 9830A calculator. The diagnostic aspect of the program uses 646 words, a further 86 words being used to run this program. The traditional and the programmed reporting procedures were duplicated for 296 consecutive patients, with no case of disagreement between the two reporting methods as to the appropriate phenotype. The programmed system requested nine repeat analyses more than did the traditional method. Seven of these were due to the tight limits set in the program for the fluoride inhibitor numbers. These tight limits were set to ensure that there was as limited an overlap as possible between the phenotypes E1uE1u and E1uE1f. The remaining two repeats were due to the restrictions placed on the succinyldicholine inhibitor numbers that would be acceptable before a patient was designated as having the relatively rare phenotype, E1aE1f.

Cholinesterases↗

PubMed2004

The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis.

Sphingosine-1-phosphate (S1P) elicits diverse cellular responses through a family of G-protein-coupled receptors. We have shown previously that genetic disruption of the S1P(1) receptor, the most widely expressed of the family, results in embryonic lethality because of its key role within endothelial cells in regulating the coverage of blood vessels by vascular smooth muscle cells. To understand the physiologic functions of the two other widely expressed S1P receptors, we generated S1P(2) and S1P(3) null mice. Neither the S1P(2) null mice nor the S1P(3) null mice exhibited significant embryonic lethality or obvious phenotypic abnormalities. To unmask possible overlapping or collaborative functions between the S1P(1), S1P(2), and S1P(3) receptors, we examined embryos with multiple S1P receptor mutations. We found that S1P(1) S1P(2) double null and S1P(1) S1P(2) S1P(3) triple null embryos displayed a substantially more severe vascular phenotype than did embryos with only S1P(1) deleted. We also found partial embryonic lethality and vascular abnormalities in S1P(2) S1P(3) double null embryos. Our results indicate that the S1P(1), S1P(2) and S1P(3) receptors have redundant or cooperative functions for the development of a stable and mature vascular system during embryonic development.

Animals↗

PubMed2025

Dissecting the shared genetic architecture of schizophrenia with ventricular subregion volumes.

Schizophrenia is characterized by cerebral ventricular enlargement as an early and consistent structural anomaly. While genetic factors significantly influence both schizophrenia and cerebral ventricular enlargement, the shared genetic etiology between them requires further investigation. Using summary statistics from recent large genome-wide association studies on schizophrenia and 9 ventricular subregion volumes phenotypes. Gaussian causal mixture modeling was applied to characterize the genetic architecture and overlap between schizophrenia and ventricular subregion volumes phenotypes. Local genetic correlation was investigated with Local Analysis of Variant Association. The conjunctional false discovery rate framework was used to identify the specific shared genetic loci, annotated with FUMA. Gaussian causal mixture modeling estimated schizophrenia to be more polygenic more polygenic (9574 trait-influencing variants) than ventricular subregion volumes phenotypes (157-1267 trait-influencing variants). Conjunctional false discovery rate analysis identified 42 shared genetic loci, 17 loci were identified as novel for both schizophrenia and the ventricular subregion volumes phenotypes. Local Analysis of Variant Association revealed that 11 distinct loci demonstrated significant differences, among which 4 loci were situated in the Major Histocompatibility Complex region. Annotated genes in shared loci were enriched in molecular signaling pathways involved in inflammation and the brain structure. The shared loci between them were annotated and enriched in Major Histocompatibility Complex and inflammation-related pathways, highlighting new opportunities for future investigation.

Schizophrenia↗

PubMed2004

Defective neural tube closure and anteroposterior patterning in mice lacking the LIM protein LMO4 or its interacting partner Deaf-1.

LMO4 belongs to a family of transcriptional regulators that comprises two zinc-binding LIM domains. LIM-only (LMO) proteins appear to function as docking sites for other factors, leading to the assembly of multiprotein complexes. The transcription factor Deaf-1/NUDR has been identified as one partner protein of LMO4. We have disrupted the Lmo4 and Deaf-1 genes in mice to define their biological function in vivo. All Lmo4 mutants died shortly after birth and showed defects within the presphenoid bone, with 50% of mice also exhibiting exencephaly. Homeotic transformations were observed in Lmo4-null embryos and newborn mice, but with incomplete penetrance. These included skeletal defects in cervical vertebrae and the rib cage. Furthermore, fusions of cranial nerves IX and X and defects in cranial nerve V were apparent in some Lmo4(-/-) and Lmo4(+/-) mice. Remarkably, Deaf-1 mutants displayed phenotypic abnormalities similar to those observed in Lmo4 mutants. These included exencephaly, transformation of cervical segments, and rib cage abnormalities. In contrast to Lmo4 nullizygous mice, nonexencephalic Deaf-1 mutants remained healthy. No defects in the sphenoid bone or cranial nerves were apparent. Thus, Lmo4 and Deaf-1 mutant mice exhibit overlapping as well as distinct phenotypes. Our data indicate an important role for these two transcriptional regulators in pathways affecting neural tube closure and skeletal patterning, most likely reflecting their presence in a functional complex in vivo.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Modification by ageing of the tetrodotoxin-sensitive sodium channels in rat skeletal muscle fibres.

Ageing leads to an impairment of muscle performance that may result from alteration of sarcolemma excitability. Therefore, we compare sodium channels of native fast-twitch skeletal muscle fibres of 21-26-month-old aged rats and 4-6-month-old young-adult rats, using the patch-clamp method. Extrajunctional sarcolemma of aged-rat fibres presented a higher sodium current density than that of young-rat fibres, which resulted from the presence of a higher number of available channels per membrane area. Open probability and availability voltage-dependence of sodium channels were similar in aged- and young-rat fibres, but permeation property was altered during ageing: aged-rat muscles showed a bimodal distribution of fibres with two values of sodium-channel conductance measured between -40 and 0 mV; a young phenotype with a conductance close to 18 pS overlapping that found in young-rat fibres and an aged phenotype with a lower approximately half conductance. Current-voltage curves extended to -60 and +20 mV showed that the aged-phenotype conductance level resulted from an outward rectification occurring in these aged-rat fibres. Furthermore, in these aged-rat fibres belonging to the aged phenotype, ensemble average sodium currents showed slower activation and inactivation kinetics. Sodium currents of the two phenotypes were blocked by 100 nM tetrodotoxin, therefore excluding possible denervation effect. These age-related modifications in sodium current may contribute to the alteration of muscle excitability and function observed during the ageing process.

Aging↗

PubMed2005

Toward localizing genes underlying cerebral asymmetry and mental health.

Genome investigations of autism, attention deficit hyperactivity disorder (ADHD), and dyslexia suggest possible genetic overlap. Atypical cerebral asymmetry (ACA), the absence of the left hemisphere dominance for language, may be a shared phenotype due to genes located in regions of overlap. A binomal test is used to evaluate whether linked regions overlap more than expected by chance for 15 genome-wide scans in autism, ADHD, and dyslexia. Significant evidence of linkage overlap (P = 10(-7)) is seen for autism, ADHD, and dyslexia for seven chromosomal regions (2p11-12, 5p13, 7q22-33, 9q33-34, 13q22, 16p13, and 17p11-q11). Linkage analysis of ACA and molecular markers for 270 sibling pairs with ADHD is conducted using the Haseman-Elston statistic. Linkage analysis supports ACA as a shared phenotype with risk genes located on 9q33-34 or 16p13 (P < 0.004). Further support stems from the overlap of these regions in schizophrenia, bipolar illness, specific language impairment (SLI), and handedness, all traits associated with ACA. Autism, ADHD, and dyslexia share regions of linkage overlap and ACA may be a shared phenotype for such genes similar to HLA in autoimmune disease. Because ACA is associated with certain aspects of creativity, such risk genes may also be enhancer genes for creativity.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Asthma: defining of the persistent adult phenotypes.

The common disease asthma is probably not a single disease, but rather a complex of multiple, separate syndromes that overlap. Although clinicians have recognised these different phenotypes for many years, they have remained poorly characterised, with little known about the underlying pathobiology contributing to them. Development of targeted therapies for asthma, and phenotype-specific clinical trials have raised interest in these phenotypes. Improved understanding of these phenotypes in complex diseases such as asthma will also improve our ability to link specific genotypes to their associated disease, which should help development of biomarkers. However, there is no standardised method to define asthma phenotypes. This Review analyses some of the methods that have been used to define asthma phenotypes and proposes an integrated method of classification to improve our understanding of these phenotypes.

Adrenal Cortex Hormones↗

PubMed1994

Role of the mixed lymphocyte culture (MLC) reaction in marrow donor selection: matching for transplants from related haploidentical donors.

The utility of the MLC assay as a test of HLA-D region matching and predictor of acute graft-versus-host disease (GvHD) was evaluated in 157 patients receiving marrow grafts from HLA-A, B identical related haploidentical donors. All donors and recipients were tested by HLA-DR serology, by Dw phenotyping with homozygous typing cells (HTC) and by standard MLC. Ninety-nine of the donor-recipient pairs were mismatched for a serologically defined HLA-DR antigen while 109 pairs were mismatched for the HLA-DR region by HTC typing. Donor antirecipient relative responses (RR) in MLC, corresponding to the GvHD vector in marrow transplantation, ranged from -4% to 100%, with a median of 25%. A comparison of reactivity in MLC with presence or absence of matching by Dw phenotyping, however, showed a significant overlap in the distribution of RRs from HLA-Dw matched versus Dw mismatched pairs, suggesting that the MLC was not a reliable predictor of HLA-Dw matching. Using an optimally-defined cutoff of 3% RR, the MLC was correlated with risk of developing clinically significant grades II-IV acute GvHD (p = 0.03) but not with risk of developing severe grades III-IV GvHD (p = 0.18). In contrast, matching by Dw phenotype was a significant predictor of GvHD, with Dw-compatible transplant recipients less likely to develop either grades II-IV (p = 0.004) or III-IV (p = 0.036) GvHD than Dw-incompatible transplant recipients. Overall, these results underscore the difficulty in using the MLC to measure HLA-D region compatibility and predict the risk of severe graft-versus-host disease among patients receiving related haploidentical marrow grafts. HLA-D (HTC) typing results correlate primarily with DRB compatibility, and with the advent of DRB1 allele matching by sequence-specific oligonucleotide probes (SSOP) or by direct sequencing, the precision in donor matching achievable with these methods is far greater than with either HLA-D typing or direct MLC testing.

Adolescent↗

PubMed2000

A general procedure for predicting rates of inbreeding in populations undergoing mass selection.

Predictions of rates of inbreeding (DeltaF), based on the concept of long-term genetic contributions assuming the infinitesimal model, are developed for populations with discrete or overlapping generations undergoing mass selection. Phenotypes of individuals are assumed to be recorded prior to reproductive age and to remain constant over time. The prediction method accounts for inheritance of selective advantage both within and between age classes and for changing selection intensities with age. Terms corresponding to previous methods that assume constant selection intensity with age are identified. Predictions are accurate (relative errors < or =8%), except for cases with extreme selection intensities in females in combination with high heritability. With overlapping generations DeltaF reaches a maximum when parents are equally distributed over age classes, which is mainly due to selection of the same individuals in consecutive years. DeltaF/year decreases much more slowly compared to DeltaF/generation as the number of younger individuals increases, whereas the decrease is more similar as the number of older individuals increases. The minimum DeltaF (per year or per generation) is obtained when most parents were in the later age classes, which is mainly due to an increased number of parents per generation. With overlapping generations, the relationship between heritability and DeltaF is dependent on the age structure of the population.

Inbreeding↗

PubMed2001

Facial and skeletal malformations, mental retardation, aganglionosis, and neurogenic muscle weakness: a variant of Niikawa-Kuroki syndrome or a new syndrome?

We report a 10-year-old boy with multiple congenital anomalies/mental retardation syndrome, who also presented with aganglionosis and neurogenic muscle weakness. Some phenotypic manifestations of our patient overlap with those observed in the Niikawa-Kuroki syndrome; however, the hypothesis of a new distinct entity, with simultaneous involvement of the central and peripheral nervous system, is considered.

Abnormalities, Multiple↗

PubMed2004

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia.

Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs (P = 0.0006) and for a combined trait of HDL-C and TGs (P = 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and TGs.

Adult↗

PubMed2000

ATM-dependent phosphorylation of nibrin in response to radiation exposure.

Mutations in the gene ATM are responsible for the genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar dysfunction, radiosensitivity, chromosomal instability and cancer predisposition. Both the A-T phenotype and the similarity of the ATM protein to other DNA-damage sensors suggests a role for ATM in biochemical pathways involved in the recognition, signalling and repair of DNA double-strand breaks (DSBs). There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS). The protein defective in NBS, nibrin (encoded by NBS1), forms a complex with MRE11 and RAD50 (refs 1,2). This complex localizes to DSBs within 30 minutes after cellular exposure to ionizing radiation (IR) and is observed in brightly staining nuclear foci after a longer period of time. The overlap between clinical and cellular phenotypes in A-T and NBS suggests that ATM and nibrin may function in the same biochemical pathway. Here we demonstrate that nibrin is phosphorylated within one hour of treatment of cells with IR. This response is abrogated in A-T cells that either do not express ATM protein or express near full-length mutant protein. We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association as revealed by radiation-induced foci formation. Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS.

Ataxia Telangiectasia↗

PubMed2005

Ullrich congenital muscular dystrophy and Bethlem myopathy: clinical and genetic heterogeneity.

UNLABELLED: Ullrich congenital muscular dystrophy (UCMD), due to mutations in the collagen VI genes, is an autosomal recessive form of CMD, commonly associated with distal joints hyperlaxity and severe course. A mild or moderate involvement can be occasionally observed. OBJECTIVE: To evaluate the clinical picture of CMD patients with Ullrich phenotype who presented decreased or absent collagen VI immunoreactivity on muscular biopsy. RESULTS: Among 60 patients with CMD, two had no expression of collagen V and their clinical involvement was essentially different: the first (3 years of follow-up) has mild motor difficulty; the second (8 years of follow-up) never acquired walking and depends on ventilatory support. A molecular study, performed by Pan et al. at the Thomas Jefferson University, demonstrated in the first a known mutation of Bethlem myopathy in COL6A1 and in the second the first dominantly acting mutation in UCMD and the first in COL6A1, previously associated only to Bethlem myopathy, with benign course and dominant inheritance. CONCLUSION: Bethlem myopathy should be considered in the differential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed.

Adolescent↗