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PubMed1992

The specificity and efficiency of endogenous peptides in the induction of HLA class I alpha chain refolding.

The specificity and efficiency of endogenous peptides in the HLA class I binding have been investigated by the use of a simple procedure that is based on the serological detection of the folding of HLA class I alpha chains that is induced by the binding to specific peptides in the presence of beta 2 microglobulin. HLA class I proteins were solubilized with a nonionic detergent from cultured HLA homozygous B lymphoblastoid cells and dissociated by alkaline denaturation. The resulting unfolded alpha chains were isolated by gel filtration at a neutral pH. The unfolded alpha chains showed a high refolding capacity and specificity when tested in the presence of an excess beta 2 microglobulin against endogenous peptides extracted by alkaline or acid treatment from cultured B lymphoblastoid cells of various HLA class I phenotypes. Cells of identical or overlapping HLA phenotypes clearly showed shared peptides, whereas such peptide sharing was rarely, if at all, seen between cells of non-overlapping HLA phenotypes. The efficiency of endogenous peptides in the induction of refolding was high; at an estimated concentration of 0.2 microM or less, a strong refolding effect was observed.

Alleles↗
PubMed2006

SERRATE: a new player on the plant microRNA scene.

MicroRNAs (miRNAs) function as sequence-specific guides that control gene expression by post-transcriptional gene silencing. Many miRNAs influence plant development by regulating the accumulation of transcripts that encode transcription factors. Mutants defective in miRNA accumulation, such as dcl1, hen1, hyl1 and ago1, have pleiotropic developmental phenotypes. The serrate-1 (se-1) mutant of Arabidopsis also shows a highly pleiotropic phenotype, which overlaps with the phenotypes of mutants defective in miRNA accumulation. Although it has been proposed that SERRATE (SE) functions specifically in miRNA-mediated repression of the leaf polarity genes PHABULOSA and PHAVOLUTA, microarray analysis shows upregulation of many genes known to be the targets of miRNAs in se-1. We show that SE is a general regulator of miRNA levels affecting the processing of primary miRNA to miRNA.

Alleles↗
PubMed2026

Phenotyping strategies for chronic overlapping pain conditions and internalizing disorders in Veterans: Prevalence, comorbidity, and latent structure as evidence for construct validity.

Chronic overlapping pain conditions (COPCs), internalizing (INT) disorders, and opioid use disorder (OUD) are common, comorbid, and difficult to phenotype at scale. Electronic health record (EHR) studies commonly define cases using Any Code (AC; ≥1 ICD-9/10 code) and Multiple Code (MC; ≥1 inpatient or ≥2 outpatient codes) phenotyping strategies, but it is unclear whether these thresholds change only case numbers or also the clinical relationships among conditions. This cross-sectional study included approximately 950,000 Million Veteran Program participants with ≥2 visits. AC and MC phenotypes for 17 conditions spanning COPCs, INT, and OUD were compared in prevalence, case characteristics, comorbidity, and latent structure. Random-thinning analysis compared AC-MC differences to case reduction alone. Construct validity was evaluated through correspondence with expected patterns of association and latent organization. Back pain (AC=58.1%; MC=48.1%), major depressive disorder (41.5%; 36.2%), and post-traumatic stress disorder (32.6%; 29.1%) were most prevalent. MC excluded 33.5% of AC cases on average, and MC cases had greater healthcare utilization, diagnostic burden, opioid exposure, and psychiatric medication use than AC-only cases. The observed mean absolute correlation change (mean |Δr|=0.014) was smaller than in all 1000 random-thinning replicates. Both strategies supported a correlated, four-factor model consistent with "Anxious Misery," "Fear," "Diffuse Pain," and "Head Pain" (AC: CFI=0.987, RMSEA=0.015; MC: CFI=0.987, RMSEA=0.014). The MC strategy reduced prevalence and altered case composition but maintained the expected comorbidity and latent organization patterns among conditions. Findings provide evidence of phenotype construct validity and inform selection of EHR phenotyping strategies for epidemiological and genomic research. PERSPECTIVE: Commonly used EHR phenotyping strategies tested in nearly one million Veterans produce broadly similar latent organization across comorbid and prevalent chronic overlapping pain conditions, internalizing disorders, and opioid use disorder. Findings support construct validity and clarify trade-offs involving case inclusion, recorded burden, and healthcare observation in large-scale research.

Chronic overlapping pain conditions↗
PubMed2003

Recent developments in the quest for myoclonic epilepsy genes.

Understanding the latest advances in the molecular genetics of the epilepsies is important, as it provides a basis for comprehending the new practice of epileptology. Epilepsies have traditionally been classified and subtyped on the basis of clinical and neurophysiologic concepts. However, the complexity and variability of phenotypes and overlapping clinical features limit the resolution of phenotype-based classification and confound epilepsy nosology. Identification of tightly linked epilepsy DNA markers and discovery of epilepsy-causing mutations provide a basis for refining the classification of epilepsies. Recent discoveries regarding the genetics surrounding certain epilepsy types (including Lafora's progressive myoclonic epilepsy, the severe myoclonic epilepsy of infancy of Dravet, and idiopathic generalized epilepsies) may be the beginning of a better understanding of how rare Mendelian epilepsy genes and their genetic architecture can explain some complexities of the common epilepsies.

Epilepsies, Myoclonic↗
PubMed1999

Dictyostelium myosin II G680V suppressors exhibit overlapping spectra of biochemical phenotypes including facilitated phosphate release.

We have biochemically characterized 13 intragenic suppressors of the G680V mutation of Dictyostelium myosin II. In the absence of the G680V mutation, the suppressors result in a number of deviant behaviors, most commonly an increase in the basal (actin-independent) ATPase of the motor. This phenotype is complementary to that of the G680V mutant and supports our proposal that the latter impairs phosphate release. Different subsets of the mutants also suffer from poor ATPase enhancement by 1 mg/ml actin, failure to release from actin in the presence of ATPgammaS (or ADP and salt), and excessive release from actin in the presence of ADP. The patterns of suppressor behaviors suggest that, in general, they are facilitating P(i)-releasing state(s) of the motor, but that different individual suppressors may secondarily perturb other states or actions of the motor.

Actins↗
PubMed1992

Xeroderma pigmentosum and Cockayne syndrome: overlapping clinical and biochemical phenotypes.

Two siblings are described whose clinical presentation of cutaneous photosensitivity and central nervous system dysfunction is strongly reminiscent of the DeSanctis-Cacchione syndrome (DCS) variant of xeroderma pigmentosum. An extensive clinical evaluation supported a diagnosis of DCS and documented previously unreported findings. In vitro fibroblast studies showed UV sensitivity that was two to three times that of normal controls. However, neither a post-UV-irradiation DNA excision-repair defect indicative of XP nor a semiconservative DNA replication defect indicative of XP variant was found. Rather, a failure of RNA synthesis to recover to normal levels after UV exposure was observed, a biochemical abnormality seen in Cockayne syndrome (CS), one of the premature-aging syndromes with clinical UV sensitivity. These patients, therefore, clinically have XP, but their biochemical characteristics suggest CS. The reason(s) for the severe neurologic disease, in light of the relatively mild cutaneous abnormalities, is unclear. Other cases with unusual fibroblast responses to irradiation have been noted in the literature and, along with the data from our patients, reinforce the notion of the complexity of DNA maintenance and repair.

Child↗
PubMed1995

Shared phenotypic expression of osteoblasts and chondrocytes in fracture callus.

Endochondral ossification in fracture healing of rats at 4, 8, 11, 14, and 21 days was analyzed using immunological and molecular probes for markers of the chondrocyte and osteoblast phenotype. These markers were osteocalcin, type I and type II collagen, including the probes homologous to the alternatively spliced forms of alpha 1 type II collagen, type IIA and type IIB. Histologic examination was performed on serial sections of the same tissue blocks to correlate cellular morphology with the immunohistochemical and in situ hybridization findings. At the junction of the cartilaginous and osseous tissue, an overlap of phenotype and morphology was noted. At the 8-day time point, the cells with chondrocyte morphology expressed intracellular message for osteocalcin and type I collagen. Immunohistochemical analysis of these cells also demonstrated intracellular osteocalcin. However, high levels of the type IIA collagen mRNA, which has previously been associated with less differentiated mesenchymal precursor cells, were expressed in both chondrocytes and osteoblasts. At the later time point (21 days) there was a substantial decrease in the number of cells displaying shared phenotypic characteristics. In situ hybridization and immunohistochemistry have permitted identification of an overlapping or shared phenotype in osteoblasts and chondroblasts in fracture callus. The findings raise important questions regarding the possible plasticity of mesenchymal cell phenotypes within the dynamic environment of fracture healing. Additional examination of these issues will further define factors involved in origin, differentiation, and maturation of bone and cartilage cells.

Animals↗
PubMed2004

[Bridging the genomic approach and the neurodevelopmental and neurodenerative hypothesis of schizophrenia].

Schizophrenia is hypothesized as a neurodevelopmental and neurodegenerative disorder based on the following findings. 1. MRI studies have revealed brain structural abnormalities from the onset of schizophrenia and the progress of these structural abnormalities. 2. Histopathological studies have elucidated cytoarchitectural abnormalities in schizophrenic brains without gliosis. 3. Obstetric complications are one of the risk factors for schizophrenia. 4. Relapse of schizophrenia results in a deteriorating progress of the disorder. Furthermore, data from family, twin and adoption studies show evidence of a substantial genetic component in schizophrenia, Thus, a molecular genetic study combined with a neurodevelopmental and neurodegenerative hypothesis is required to elucidate the pathophysiology of schizophrenia. The positive association between neuregulin 1 and Icelandic schizophrenia that has been reproduced in Scottish and North European schizophrenia is one of the intriguing examples of this type of research. Neuregulin 1 regulates the cytoarchitecture of brain. Mice mutated for neuregulin 1 show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, the behavioral phenotypes of the neuregulin 1 hypomorphs are reversible with clozapine. We also demonstrated a positive association between schizophrenia and a 5-HT5A receptor polymorphism, Pro15Ser, that may have role in cell differentiation in the brain.

Animals↗
PubMed2004

Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

Amino Acid Sequence↗
PubMed2004

Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus.

The authors identified two Japanese spinocerebellar ataxia (SCA) families characterized by postural and action tremor and a very slow progression rate. A genome-wide linkage analysis revealed linkage to chromosome 3p26.1-25.3 with the highest multipoint lod score at D3S3728 (Zmax = 3.31 at theta = 0.00). The candidate region was 14.7 cM flanked by D3S1620 and D3S3691, which was partly overlapping with the locus of SCA15 characterized by pure cerebellar ataxia. Despite the difference in phenotypes, there remains a possibility that the causative gene for these Japanese SCA is allelic to SCA15.

Adult↗
PubMed2006

Distinct neuromuscular phenotypes in myotonic dystrophy types 1 and 2 : a whole body highfield MRI study.

Myotonic Dystrophy Type 1 (DM1) and 2 (DM2) present with distinct though overlapping clinical phenotypes. Comparative imaging data on skeletal muscle involvement are not at present available. We used the novel technique of whole body 3.0 Tesla (T) Magnetic Resonance Imaging (MRI) to further characterize musculoskeletal features in DM2 and compared the results with DM1.MRI findings of 15 DM1 and 14 DM2 patients were evaluated with respect to patterns of skeletal muscle affection and clinical data using the Muscular Impairment Rating Scale (MIRS) and Medical Research Council scale (MRC). All DM1 patients had pathological MRI compared with only 5 DM2 patients. In contrast to DM2, DM1 patients showed a characteristic distribution of muscle involvement with frequent and early degeneration of the medial heads of gastrocnemius muscles, and a perifemoral semilunar pattern of quadriceps muscle affection sparing the rectus femoris. The most frequently affected muscles in DM1 were the medial heads of gastrocnemius, soleus, and vastus medialis muscles. In DM2, however, the erector spinae and gluteus maximus muscles were most vulnerable to degeneration. MRI data were in line with the clinical grading in 12 DM1 and 3 DM2 patients. In 3 DM1 and 5 DM2 patients, MRI detected subclinical muscle involvement. 9 DM2 patients with mild to moderate proximal muscle weakness and/or myalgias had normal MRI. Pathological MRI changes in DM2 emerged with increasing age and were restricted to women. Whole body 3.0T MRI is a sensitive imaging technique that demonstrated a characteristic skeletal muscle affection in DM1. In contrast, MRI was no reliable indicator for skeletal muscle involvement in mildly affected DM2 patients since myalgia and mild paresis were usually not reflected by MRI signal alterations.

Adolescent↗
PubMed2004

Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients.

The peroxisome biogenesis disorders (PBDs) with generalized peroxisomal dysfunction include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). There is clinical, biochemical, and genetic overlap among the three phenotypes, also known as Zellweger spectrum disorders. Clinical distinctions between the phenotypes are not sharply defined. Only limited sources are available to serve as a background for prognosis in PBD, especially in case of prolonged survival. We delineated the natural history of 31 PBD patients (age 1.2-24 years) through systematic clinical and biochemical investigations. We excluded classical ZS from our study, and included all patients with a biochemically confirmed generalized peroxisomal disorder over 1 year of age, irrespective of the previously diagnosed phenotype. The initial clinical suspicion, age at diagnosis, growth, development, neurological symptoms, organ involvements, and survival are summarized. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure, 10 patients displayed hyperoxaluria of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from non-verbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties as outcome profiles. At the molecular level, 21 patients had mutations in the PEX1 gene. The two most common PEX1 mutations were the G843D (c.2528G-->A) missense and the c.2097insT frameshift mutation. Patients having the G843D/G843D or the G843D/c.2097insT genotypes were compared. Patients homozygous for G843D generally had a better developmental outcome. However, one patient who was homozygous for the "mild" G843D mutation had an early lethal disease, whereas two other patients had a phenotype overlapping with the G843D/c.2097insT group. This indicates that next to the PEX1 genotype other yet unknown factors determine the ultimate phenotype.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2004

Hodgkin lymphoma with unusual intrasinusoidal pattern of infiltration.

In spite of recent great advances in our understanding of both Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL), occasionally there are CD30-positive large cell hematopoietic neoplasms, in which the morphologic and phenotypic features overlap to such an extent that they cannot easily be classified. We report a histologically unusual case of HL that mimicked ALCL, but had phenotypical characteristics of HL. The neoplastic cells resembling Reed-Sternberg cells or Hodgkin cells were mainly situated within sinusoidal spaces, which are characteristically seen in ALCL. However, they showed unequivocal expression of both CD30 and CD15, and no aberrant antigen expression to suggest ALCL (BSAP+, EMA-, LCA-, CD43-, CD2-, CD3-, CD4-, CD45RO-, ALK-, granzymeB-), with negative TCR gene rearrangement and no expression of EBV. HL with intrasinusoidal pattern has rarely been described, but we suggest that, although cases of HL with such a striking sinusoidal pattern are rare, nevertheless do exist. Since the identification of sinusoidal infiltration by CD30-positive neoplastic cells may lead to a mistaken view of ALCL, wide panel of antibodies should be used to confirm the diagnosis.

Diagnosis, Differential↗
PubMed1998

Diversity of hemagglutination phenotypes among P-fimbriated wild-type strains of Escherichia coli in relation to papG allele repertoire.

Data regarding the hemagglutination (HA) patterns of the three variants (classes I, II, and III) of the Escherichia coli adhesin PapG are conflicting. These HA patterns usually have been assessed for each papG allele separately with recombinant strains in slide HA assays. We rigorously evaluated an alternative microtiter tray HA assay and then used it to assess the HA of four erythrocyte types (human A1P1 and OP1, rabbit, and sheep erythrocytes) by multiple wild-type E. coli strains representing the four naturally occurring combinations of the papG alleles, i.e., class I plus III, class III only, class II plus III, and class II only. The microtiter tray HA assay displayed significantly better reproducibility of intraobserver (83%) and interobserver (86%) results than did slide HA assays (39 and 73%, respectively). Novel findings from the study of 32 wild-type P-fimbriated strains included reproducible determinations of phenotypic diversity among different papG categories, among strains within each papG category, and from day to day for individual strains. There was also substantial overlap of phenotypes between papG categories I plus III and III only and between II plus III and II only. A class III papG recombinant strain's HA pattern differed significantly from that of the wild-type class III strains. These data demonstrate that HA phenotypes of wild-type P-fimbriated E. coli strains can be reproducibly assessed by a microtiter HA assay and that they correspond broadly to papG genotype but in a more complex and varied fashion than previously recognized.

Adhesins, Escherichia coli↗
PubMed2002

Neuregulin 1 and susceptibility to schizophrenia.

The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

Animals↗
PubMed2005

Speculations on the pathogenesis of CHARGE syndrome.

To be seriously considered, a theory about the pathogenesis of a multiple congenital anomaly syndrome should meet three criteria: (1) it should explain all of the anomalies associated with the syndrome; (2) it should explain why certain anomalies are not associated with the syndrome; and (3) it should predict anomalies that could be associated with the syndrome, but have not yet been described. The theory must eventually pass the ultimate test, that is, molecular confirmation of the proposed mechanism. Several theories about the pathogenesis of CHARGE syndrome have been proposed, but none of these meet the three criteria stated above. In this study, the author proposes that CHARGE syndrome is due to a disruption of mesenchymal-epithelial interaction (epithelial includes ectoderm and endoderm). The theory is tested against the major, minor, and occasional anomalies that are used to make the clinical diagnosis of CHARGE syndrome. Review of the known embryology of the organs and tissues involved in CHARGE syndrome confirms that mesenchymal-epithelial interactions are necessary for proper formation of these organs and tissues. The presence of limb anomalies in approximately one-third of CHARGE syndrome patients fulfills criteria #3 above, in that limb anomalies were not felt to be a part of CHARGE syndrome until relatively recently. It is known that some patients with chromosomal abnormalities have a phenotype that overlaps with CHARGE syndrome. Given that critical developmental pathways must be robust and redundant in order to minimize errors, it may be that disruption of more than one gene is necessary to generate the CHARGE phenotype, as has been proposed for the holoprosencephaly sequence. Mutations and deletions of CHD7 have recently been identified as causing CHARGE syndrome in more than 50% of tested patients. Given this gene classes' putative role as a general controller of developmental gene expression as well as mesodermal patterning, it would fit the hypothesized mechanisms discussed in the study.

Abnormalities, Multiple↗