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At least 271 records · Page 15Linked to original sources
PubMed2004

Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity.

Endothelial cells have been shown to activate T cell responses to alloantigens, triggering transplant rejection. However, they may also play a role in tolerance induction. Using RT-PCR we show here that alloantigen specific CD8(+)CD28(-) T suppressor cells generated in vitro are FOXP3 positive and interact with human endothelial cells. This interaction results in the induction of inhibitory receptors and down-regulation of costimulatory and adhesion molecules, thus rendering endothelial cells tolerogenic. In turn, tolerized endothelial cells elicit the differentiation of CD8(+)CD28(-) FOXP3(+) T suppressor cells. Taken together our data demonstrate a functional and phenotypic overlap between tolerogenic dendritic cells and endothelial cells. Furthermore, alloantigen specific CD8(+)CD28(-) FOXP3(+) T cells, which trigger the upregulation of inhibitory receptors in endothelial cells, are present in the circulation of heart allograft recipients in quiescence as demonstrated by flow cytometry, RT-PCR and luciferase transcription assays. Their detection facilitates the identification of patients who may benefit from partial or complete cessation of immunosuppressive therapy, a goal of obvious importance given the morbidity and mortality associated with chronic immunosuppression. Modulation of endothelial cells in favor of promoting tolerance may be important for long-term survival of organ allografts.

Adult↗
PubMed2002

Distinct palindromic extensions of the 5'-TTC...GAA-3' motif allow STAT6 binding in vivo.

STATs (signal transducers and activators of transcription) are transcription factors downstream of cytokine and growth factor signals. All of the seven different STATs bind to regulatory promoter elements with the common core motif 5'-TTC(N)2-4GAA-3'. A key question is how the different STAT factors recognize "their" response elements, that is, what distinguishes for example STAT1 from STAT6 binding sites. In vivo, binding of the different STATs to DNA elements is highly specific and disruption of the genes for the different STAT factors is accompanied with distinct, non-overlaping phenotypical effects. As a first step towards discrimination of target sequences for the various STATs, we determined requirements for binding sites for STAT6. In functional assays, six sequences were identified. These have palindromic extensions of the core motif in common (underlined): 5'-TTTCNNNGAAA-3', 5'-CTTCNNNGAAG-3', 5'-TTTCNNNNGAAA-3', 5'-CTTCNNNNGAAG-3', 5'-TTCCNNGGAA-3' and 5'-TTCANNTGAA-3'. Different approaches and mutational analysis demonstrated the functionality of these sequences and high specific binding to STAT6. (I) These elements mediate transcriptional induction by interleukin-(IL)-4, IL-13, IL-15, and platelet-derived growth factor. (II) When used as "decoy" oligonucleotides, they bind STAT6 and disrupt its function in vivo, attenuating (a) STAT6/IL-4-mediated reporter gene transcription and (b) STAT6/IL-4-mediated induction of mu-opioid receptor mRNA of Raji cells.

Base Sequence↗
PubMed2001

"Juvenile" xanthogranuloma: an immunophenotypic study with a reappraisal of histogenesis.

The non-Langerhans histiocytoses, a nosologic category to which juvenile xanthogranuoma (JXG) belongs, represent a heterogenous collection of disorders related to the monocyte/macrophage lineage. The dermal dendrocyte was previously proposed as the cell of origin for JXG on the basis of Factor XIIIa reactivity, a suggestion that does not fully explain the occasional xanthogranulomatous proliferations localizing exclusively to extracutaneous sites. This study applies a panel of recently developed immunohistochemical markers to JXGs and relates the phenotype of this process to new concepts of monocyte/dendritic cell ontogeny. Twenty-seven JXG, ten dermatofibromas (DF), and ten age-matched normal skin specimens were stained using standard immunohistochemistry methods, and all JXGs were fascin+ and CD68+, although 26 of 27 were reactive for HLA-DR, 25 of 27 for Factor XIIIa, 25 of 27 for LCA, 21of 27 for CD4, and 8 of 27 for polyclonal s100. Six of those eight polyclonal S100+ cases were also reactive for monoclonal S100. None of those cases was reactive for CD1a, CD3, CD21, CD34, or CD35. Eight of ten dermatofibromas were FXIIIa+; all were negative for HLA-DR, LCA, CD4, and polyclonal s100. In controls, fascin+ dendritic cells were present but did not stain for Factor XIIIa, S100, or CD4. Based on the morphologic and phenotypic overlap of the lesional cells in JXGs and plasmacytoid monocytes, it would appear that the plasmacytoid monocyte might be considered the putative normal counterpart of the major cellular population of JXGs, a proposal that helps explain the extra-cutaneous, visceral, and soft tissue location that have been reported for occasional cases of JXG. We would also conclude that neither Factor XIIIa-nor S100+ results should preclude the diagnosis of JXG, and find that reactivity for CD4 and LCA may be used to distinguish JXG from DF when the latter is heavily lipidized or the former is not.

Adolescent↗
PubMed1998

Pigmented ("black") extraadrenal paraganglioma.

A pigmented ("black") extraadrenal paraganglioma was discovered incidentally in a 57-year-old woman during ultrasonography. The tumor was located in the retroperitoneum near the superior border of the right kidney. Results of preoperative fine-needle aspiration and intraoperative frozen sectioning of the resected jet-black tumor (13 cm in diameter, 225 g) were both interpreted as suspicious for malignant melanoma. Histomorphology and immunohistochemistry were diagnostic for paraganglioma. Electron microscopy showed numerous dense-core neurosecretory-type granules, as well as abundant, larger pleomorphic electron-dense granules; most were consistent with lipofuscin or neuromelanin. No melanosomes or premelanosomes were identified. Histochemical stains showed that the pigment most likely is neuromelanin, a nonenzymatic or oxidative waste product of catecholamine metabolism. Eighteen other examples of pigmented paragangliomas have been reported in various sites in the English literature during the last 12 years; most indicate the presence of melanosomes or premelanosomes using electron microscopy, whereas in a minority of cases the pigment has not been characterized rigorously. Common embryogenesis from neural crest may help explain the overlapping phenotype of melanocytes and cells of paraganglioma.

Female↗
PubMed2004

Laminopathies: from the heart of the cell to the clinics.

PURPOSE OF REVIEW: This review outlines recent advances in the clinical, genetic and molecular aspects of laminopathies, an expanding group of disorders caused by mutations of the lamin A/C gene. RECENT FINDINGS: Mutations in lamin A/C were originally described in skeletal and cardiac muscle disorders. It has subsequently been shown that partial lipodystrophy syndromes with or without developmental abnormalities and premature ageing are also associated with lamin A/C alterations. Concomitantly, peripheral nerve involvement with autosomal recessive and dominant inheritance is adding to the picture. The clinical heterogeneity of laminopathies ranges from intrafamilial variability to the description of overlapping phenotypes. A large variability in clinical presentation and the course of cardiomyopathy occurs, including sudden death despite pacemaker implant and embolic stroke in young patients. Similarly, premature ageing syndromes encompass classic and atypical forms of varying severity with the involvement of diverse tissues. In addition, an association of myopathic and neuropathic phenotypes is now emerging. SUMMARY: Advances in molecular genetics of apparently unrelated disorders, involving muscle, heart, nerve, fat, bone, liver, skin tissues and premature ageing, have enriched our knowledge of the diverse phenotypes associated with lamin A/C mutations. Nevertheless, the understanding of pathogenetic mechanisms still remains speculative. More basic and clinical research is needed in order to identify genes concurring in determining the lamin A/C phenotypes and to envisage proper treatment strategies.

Animals↗
PubMed2002

A Schinzel-Giedion-like syndrome--a milder version or a separate condition?

We report two 12-year-old monozygotic twins followed from birth. Their features include midface hypoplasia, a prominent forehead, coarse features, sensorineural deafness, short stature with thoracic kyphosis and lumbar lordosis and intellectual delay. As they have developed, their features have been reminiscent of a storage disorder but mucopolysaccharidoses, mucolipidoses and gangliosidoses have been excluded by biochemical testing. We discuss the phenotypic overlap with the Schinzel-Giedion syndrome but highlight the important differences. Individuals with Schinzel-Giedion syndrome tend to have renal and cardiac malformations and to have a very poor outlook, often dying in the first 3 years of life. We suggest that these twins have a previously undescribed Schinzel-Giedion like syndrome.

Abnormalities, Multiple↗
PubMed2006

3-M syndrome: a report of three Egyptian cases with review of the literature.

The 3-M syndrome is a rare autosomal recessive disorder. It is characterized by prenatal and postnatal growth retardation associated with characteristic features. In this study, we report on three patients from two unrelated families, including two male sibs, with the characteristic features and radiological findings of the 3-M syndrome. The main features in our cases were low birth weight, short stature, malar hypoplasia, anteverted nostrils with a fleshy nasal tip, long philtrum, pointed full chin, short broad neck, broad chest with transverse grooves of anterior thorax and hyperlordosis. An orodental examination revealed characteristic findings, some of which were not reported before. Prominent premaxilla, hypoplastic maxilla, thick patulous lips, high-arched palate, median fissured tongue, delayed eruption of teeth with enamel hypocalcification and malocclusion were present in our three studied cases. Radiographic studies showed slender long bones and ribs, a narrow pelvis and foreshortened vertebral bodies. Our reported cases are the offspring of healthy consanguineous parents, confirming the autosomal recessive pattern of inheritance in the syndrome. Cases were reported from different countries all over the world. To our knowledge, these are the first reported Egyptian patients with this rare disorder. This syndrome may be underreported because of the phenotypic overlap with other low birth dwarfism syndromes. Recent identification of a gene mutated in some cases of 3-M syndrome will aid diagnosis.

Abnormalities, Multiple↗
PubMed2004

Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors.

Malignant rhabdoid tumor (MRT) is a highly aggressive neoplasm that occasionally demonstrates phenotypic overlap with other soft tissue malignancies. Molecular genetic analysis of MRT frequently demonstrates deletion or mutation of the hSNF5/INI1 gene, with corresponding reduced expression at the protein level. INI1 immunohistochemistry was performed to determine the utility of this method in assessing loss of INI1 expression in rhabdoid tumors. Twenty-seven MRTs with molecular analysis (19 renal, 8 extra-renal) were evaluated. Seventeen additional MRT (10 renal, 7 extra-renal) without INI1 molecular analysis were also analyzed. Loss of INI1 expression was observed in the tumor cells in all 44 cases. To determine the specificity of this assay, a variety of 45 pediatric soft tissue tumors, some of which occasionally display rhabdoid differentiation, were investigated. These included Ewing's sarcoma, Wilms' tumor, desmoplastic small round cell tumor, clear cell sarcoma, congenital mesoblastic nephroma, synovial sarcoma, undifferentiated sarcoma, rhabdomyosarcoma, and epithelioid sarcoma. Positive nuclear staining was found in all nonrhabdoid tumors examined. Of interest, synovial and epithelioid sarcomas exhibited variable and/or focal staining. INI1 antibody immunohistochemistry is useful in confirming the histologic diagnosis of renal or extra-renal rhabdoid tumor, especially for cases with indeterminate histologic features, equivocal immunophenotypic profiles, or uninformative molecular studies.

Adolescent↗
PubMed1998

Direct selection of conserved cDNAs from the DiGeorge critical region: isolation of a novel CDC45-like gene.

We have used a modified direct selection technique to detect transcripts that are both evolutionary conserved and developmentally expressed. The enrichment for homologous mouse cDNAs by use of human genomic DNA as template is shown to be an efficient and rapid approach for generating transcript maps. Deletions of human 22q11 are associated with several clinical syndromes, with overlapping phenotypes, for example, velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS). A large number of transcriptional units exist within the defined critical region, many of which have been identified previously by direct selection. However, no single obvious candidate gene for the VCFS/DGS phenotype has yet been found. Our technique has been applied to the DiGeorge critical region and has resulted in the isolation of a novel candidate gene, Cdc45l2, similar to yeast Cdc45p. [The sequence data described in this paper have been submitted to the EMBL data library under accession nos. AJ0223728 and AF0223729.]

Amino Acid Sequence↗
PubMed1989

A Unique Phenotype in Heterozygotes of the Auxin-Insensitive Mutant of Tomato, diageotropica.

Tomato (Lycopersicon esculentum Mill.) plants heterozygous for the diageotropica (dgt) mutation exhibit a unique phenotype, termed ;mottled.' Unlike dgt, mottled individuals grow upright, exhibit normal root branching, and produce normal levels of ethylene in response to applied auxin. Leaves of mottled plants are deformed and reduced in size and are characterized by a mottled appearance on their surfaces with small dark-green islands clustered along the leaf veins. The lack of phenotypic overlap between dgt and mottled may represent interallelic interaction at a locus which influences auxin sensitivity or action in the tomato.

Journal Article↗
PubMed2000

Evolution of temporal isolation in the wild: genetic divergence in timing of migration and breeding by introduced chinook salmon populations.

The timing of migration and breeding are key life-history traits; they are not only adaptations of populations to their environments, but can serve to increase reproductive isolation, facilitating further divergence among populations. As part of a study of divergence of chinook salmon, Oncorhynchus tshawytscha, populations, established in New Zealand from a common source in the early 1900s, we tested the hypotheses that the timing of migration and breeding are under genetic control and that the populations genetically differ in these traits despite phenotypic overlap in timing in the wild. Representatives of families from two populations were collected within a day or two of each other, reared in a common environment, and then released to sea from each of two different rivers, while other family representatives were retained in fresh water to maturity. The date of maturation of fish held in fresh water and the dates of return from the ocean and maturation of fish released to sea all showed significant differences between the two populations and among families within populations. The very high heritabilities and genetic correlations estimated for migration and maturation date indicated that these traits would respond rapidly to selection. Combined with the results of related studies on these chinook salmon populations, it appears that spawning time may not only evolve during the initial phases of divergence, but it may play an important role in accelerating divergence in other traits.

Animals↗
PubMed1992

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B.

The availability of MoAbs now allows the accurate quantification of the individual C4 isotypes, C4A and C4B. Using a sensitive two-site immunoradiometric technique to measure serum levels of C4A and C4B, we studied the relationship between genotype and phenotype and physiological factors affecting C4 expression in 129 fully genotyped healthy subjects. Our results confirm that there is extensive phenotypic overlap between genotypic groups and it was not possible to determine the presence of single null alleles from total serum C4. Of the factors which may influence C4 expression, we found that age contributes a very small influence but that gender has no effect and there was no evidence for the presence of feedback of null alleles on the expression of remaining genes. Potential problems in quantifying C4 arising from the complex relationship between isotypic identity and serotypic recognition were highlighted by the finding of reversed antigenic expression of a C4B*5 molecule which was recognized as C4A by the anti-Rg:1 monoclonal used in these studies. We also confirmed that the extended MHC haplotype associated with Felty's syndrome, HLA-B44, C4A*3, C4BQ*O, HLA-DR4, encodes an expressed, duplicated, C4A gene.

Adult↗
PubMed2004

Modulation of GDF5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2.

The brachydactylies are a group of inherited disorders of the hands characterized by shortened digits. Mutations in the tyrosine kinase receptor Ror2 cause brachydactyly type B (BDB). Mutations in GDF5, a member of the BMP/TGF-beta ligand family, cause brachydactyly type C (BDC) whereas mutations in the receptor for GDF5, BRI-b, cause brachydactyly type A2 (BDA2). There is considerable degree of phenotypic overlap between the subtypes BDB, BDC and BDA2. Here we demonstrate that all three components are involved in GDF5 induced regulation of chondrogenesis. We show that Ror2 (tyrosine kinase receptor) and BRI-b (serine/threonine kinase receptor) form a ligand independent heteromeric complex. The frizzled-like-CRD domain of Ror2 is required for this complex. Within that complex Ror2 gets transphosphorylated by BRI-b. We show that Ror2 modulates GDF5 signalling by inhibition of Smad1/5 signalling and by activating a Smad-independent pathway. Both pathways however, are needed for chondrogenic differentiation as demonstrated in ATDC5 cells. The functional interaction of Ror2 with GDF5 and BRI-b was genetically confirmed by the presence of epistatic effects in crosses of Ror2, BRI-b and Gdf5 deficient mice. These results indicate for the first time a direct interaction of Ser/Thr- and Tyr-Kinase receptors and provide evidence for modulation of the Smad-pathway and GDF5 triggered chondrogenesis.

Animals↗
PubMed1993

Divergent differentiation in small round-cell tumours of the soft tissues with neural features--an analysis of 10 cases.

A series of 10 small round-cell tumours, having in common evidence of neural differentiation, were investigated by immunohistochemistry and electronmicroscopy. In seven, evidence of divergent muscle and/or epithelial differentiation was found. This phenomenon thus appears more common than previously appreciated and suggests that there may be a continuous and overlapping phenotypic spectrum from Ewing's tumour of soft tissue to intra-abdominal desmoplastic small cell tumour.

Adolescent↗
PubMed2004

Autism in Angelman syndrome: implications for autism research.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, ataxia, and a happy/sociable disposition. Maternally, but not paternally, derived defects, such as duplications, within the AS critical region result in autistic symptomatology, suggesting that the UBE3A gene might be implicated in the causation of autism. This study examined the prevalence of autism in AS in 19 children representing three known molecular classes of AS. Children were studied over the course of 1 year. Forty-two percent of this population, eight of 19 children, met criteria for autism according to the Autism Diagnostic Observation Schedule (ADOS). Parents of children who were diagnosed with autism according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria as well as the ADOS - Generic, Module 1 (ADOS-G) were administered the Autism Diagnostic Interview - Revised (ADI-R). Data from the ADI-R were convergent with data from the ADOS-G in all cases. Children with comorbid autism and AS scored lower on measures of language, adaptive behavior, and cognition, and demonstrated a slower rate of improvement over the course of the study. Furthermore, they demonstrated deficits in communication and socialization that mirror those observed in children with idiopathic autism. The study highlights the phenotypic overlap between autism and AS and increases the probability that dysregulation of UBE3A may play a role in the causation of autism.

Angelman Syndrome↗
PubMed2006

LADD syndrome is caused by FGF10 mutations.

Lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] is an autosomal-dominant multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies. Loss of function mutations in FGF10 were recently described in aplasia of the lacrimal and salivary glands [ALSG (MIM 180920; MIM 103420)] (Entesarian et al., Nat Genet 2005: 37: 125-127, Milunsky et al., American College of Medical Genetics Annual Meeting, Dallas, TX, 2005: A100). Due to the significant phenotypic overlap between LADD syndrome and ALSG and the variable expressivity of both the disorders, we hypothesized that FGF10 mutations could also result in LADD syndrome. A de novo missense mutation was found in exon 3 of FGF10 in a 3-year-old female (Family 1) with LADD syndrome. This missense mutation, resulting in a non-conservative amino acid change, was confirmed by restriction enzyme digestion and was not found in 500 control chromosomes. A nonsense mutation was also found in exon 2 of FGF10 (Family 2) in a 19-year-old mother with ALSG and her 2-year-old daughter with LADD syndrome. Previous studies of FGF10 mutant mice have demonstrated abnormalities consistent with ALSG and LADD syndrome. We conclude that ALSG and LADD syndrome may represent variable presentations of the same clinical spectrum caused by FGF10 mutations.

Abnormalities, Multiple↗
PubMed2006

Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.

Eye development initiates as an evagination of the early neural plate, before the closure of the neural tube. Structural malformations of the eye such as anophthalmia and microphthalmia arise very early in development. It is not surprising therefore that three of the genes currently identified to play a significant role in these developmental eye anomalies are also major players in brain development and regionalization. However, as has been emerging for a high proportion of transcriptional regulators studied, these genes have evolved to play multiple roles throughout development, and perhaps even in adult tissue maintenance. This complex spatiotemporal expression pattern requires elaborate regulatory systems which we are beginning to unravel. A major component of these complex regulatory networks is a series of cis-acting elements, highly conserved through evolution, which spread large distances from the coding region of each gene. We describe how cross regulation for PAX6, SOX2 and perhaps OTX2 has now been uncovered, pointing to the mechanisms that can fine-tune the expression of such essential developmental components. These interactions also help us understand why there is significant phenotypic overlap between mutations at these three loci.

Animals↗
PubMedDate not supplied

Genetic studies in azoospermic patients with the Klinefelter pattern of testicular biopsy.

82 male patients presenting functional azoospermia and klinefelter pattern of testicular biopsy were subjected to genetic, histopathologic, anthropometric and clinical studies. With finer methods of analysis, heterogeneity, within a disorder previously thought to represent one entity is usually revealed. Results of the present investigation suggest that sex chromatin counts cannot substitute chromosomal analysis for the discover of mosaiscism. The study also showed a marked phenotypic overlap between the X-chromatin positive Klinefelter disease and the X-chromatin negative Klinefelter syndrome. This overlap occurs both at the clinical level, documented by anthropometry and histopathologic findings in the testicular biopsy, emphasizing the importance of cytogenetic studies. Cases without the chromosomal aberration in whom we suspect environmental etiology may be described a sphenocopies of the genetic disorder.

Age Factors↗