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PubMed2026

A genome-wide investigation of depression among individuals with and without irritability.

Individuals presenting with both depression and irritability may constitute a different group of individuals with respect to those presenting without irritability, but their biological differences remain unknown. We aimed to identify genetic variants associated with depression among individuals with and without irritability, highlight biological pathways, and test for genetic associations with other traits. We conducted a genome-wide association study (GWAS) using data from the UK Biobank (N = 487,409). We identified a group of individuals presenting with depression and reporting never having experienced irritability (depression without irritability, n = 35,857, 11.8%), and another with depression and reporting having experienced irritability (depression with irritability, n = 23,613, 8.1%) and compared them to controls with no depression or irritability (n = 268,012). The GWAS of depression without irritability identified 2 SNPs which reached genome-wide significance (P < 5×10-8; rs72795440 and rs1233494). The GWAS of depression with irritability (NGWAS = 292,485) identified 3 SNPs reaching genome-wide significance (rs2815748, rs102275, and rs7227069). When comparing SNPs between depression phenotypes, 15 SNPs had significantly different effect sizes. Patterns of genetic correlation with 44 complex traits were overall similar between the 2 depression phenotypes, with the highest genetic overlap observed with anxiety for depression without irritability (rg = .77) and neuroticism for depression with irritability (rg = .76). This study shed light into common and distinct biological factors characterizing depression among individuals with and without irritability and contribute to better understanding the genetic architecture of depression to potentially inform treatment and personalized medicine.

Humans↗

PubMed1981

Triplex gene dosage effect of beta-glucuronidase and possible assignment to band q22 in a partial duplication 7q.

A 2-year-old girl had a de novo duplication in the long arm of one chromosome 7 and an increased level of the enzyme beta-glucuronidase in cultured fibroblasts. The phenotype of the girl partly overlaps those of two presumptive syndromes due to secondary partial trisomies 7q. The ratio of the enzyme activity was 1.43 to the controls, and 1.37 to her parent's values. We could not define the abnormality but suggest two alternatives: either the patient is trisomic for region q112 to q22 or for the region q22 to q34. If the second alternative is correct the locus for beta-glucuronidase is possibly assigned to band 7q22.

Chromosome Banding↗

PubMed2002

Molecular basis for stool-based DNA tests for colorectal cancer: a primer for clinicians.

Cancers develop as a result of alterations in genes that regulate growth, survival, and other cellular behaviors. Colorectal cancers develop through one of at least three different pathways, termed chromosomal instability, microsatellite instability, and the CpG island methylator phenotype. Although there is some overlap, these pathways tend to inactivate different sets of tumor suppressor genes and tend to have somewhat different biological behaviors. Tumor cells and DNA are shed into the fecal stream, and uniquely mutated genes can be identified that would indicate the likely presence of a neoplasm in the gastrointestinal tract. By understanding the pathways to tumor development, the target genes involved, and the mechanisms underlying genomic instability, it will be possible to implement strategies to detect and treat the different types of colorectal cancer.

Colorectal Neoplasms↗

PubMed2000

Role of Enhancer of zeste on the production of Drosophila melanogaster pheromonal hydrocarbons.

In a search for genes controlling the production of Drosophila melanogaster contact pheromones, the gene Enhancer of zeste [E(z)] was found to be one player. Flies mutant for either the amorphic or the antimorphic allele of E(z) showed a similar hydrocarbon phenotype as those with the overlapping Df lxd(15) deficiency: decreased amounts of total hydrocarbons and especially unsaturated ones in both sexes. The decrease in the level of D. melanogaster female sex pheromone 7,11-heptacosadiene was dramatic and was correlated with an increase in 7-heptacosene. Females mutant for a gain-of-function allele had increased amounts of total hydrocarbons with wild-type proportions of dienes. Thus the E(z) gene seems to affect hydrocarbon biosynthesis, especially its desaturation steps and even more so the female-specific desaturation step transforming 7-monoenic fatty acids to 7,11-dienic ones and leading to female pheromones.

Animals↗

PubMed2005

A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome.

The clinical phenotype of Ligase IV syndrome (LIG4 syndrome), an extremely rare autosomal recessive condition caused by mutations in the LIG4 gene, closely resembles that of Nijmegen breakage syndrome (NBS), and is characterized by microcephaly, characteristic facial features, growth retardation, developmental delay, and immunodeficiency. We report a 4(1/2)-year-old boy who presented with acute T-cell leukemia. The facial gestalt was strongly reminiscent of NBS. The patient died shortly after the onset of treatment for his T-cell leukemia. Subsequent chromosome breakage studies showed a high rate of breakage in a fibroblast culture. Radiosensitivity was assessed by a colony survival assay; the results showed radiosensitivity greater than is typically seen in NBS. Mutation screening of the NBS1 gene was negative. Sequencing of the LIG4 gene revealed a homozygous truncating mutation 2440 C>T (R814X). Although this mutation has been previously noted in LIG4 syndrome, this patient is the first reported homozygote for the mutation. In this study, we review the clinical features of this rare syndrome and provide suggestions for differential diagnosis.

Abnormalities, Multiple↗

PubMed2004

Septo-optic dysplasia with digital anomalies--a recurrent pattern syndrome.

A distinct form of septo-optic dysplasia (SOD) comprises limb malformations in addition to the characteristic CNS and ocular abnormalities. To date, there have been 4 reports, citing 5 affected patients with this combined phenotype. We now add a further case and present neuroradiological images of the CNS findings in this condition. The striking consistency of the limb malformations and their overlap with the Streeter's band phenotype is emphasized.

Abnormalities, Multiple↗

PubMed2001

Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain.

Throughout life, the anterior part of the postnatal rodent subventricular zone (SVZa), surrounding the lateral ventricles, contains a prolific source of neuronal progenitor cells that retain their capacity to concurrently generate neurons and migrate along the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into interneurons. This study was designed to determine whether the SVZ and RMS of the postnatal primate also harbor a specialized population of neuronal progenitors with the capacity to divide while they migrate. In order to reveal the spatial-temporal changes in the distribution and composition of the neuronal progenitor cells in the primate SVZ and RMS, seven rhesus monkeys, ranging in age from 2 days to 8 years, were given a single injection of the cell proliferation marker bromodeoxyuridine (BrdU) 3 h before they were perfused. The phenotypic identity of the BrdU(+) cells was revealed by double labeling sagittal sections with cell type-specific markers. From birth onward the distribution of BrdU(+) cells with a neuronal phenotype is extensive and largely overlapping with that of the rodent. Similar to the rodent brain the neuronal progenitors are most numerous in neonates. The BrdU(+) neurons in the primate forebrain extend lateral and ventral to the lateral ventricle and all along the RMS. The cytoarchitectonic arrangement and appearance of the neuronal progenitor cells is quite varied in the primate compared to the rodent; in some locations the cells are aligned in parallel arrays resembling the neuronal chains of the adult rodent RMS, whereas in other positions the cells have a homogeneous "honeycomb" arrangement. The chains are progressively more pervasive in older primates. Akin to the RMS of adult rodents, in the primate SVZ and RMS the astrocytes often form long tubes enveloping the chains of neuronal progenitors. Our study demonstrates that the primate forebrain, similar to the rodent forebrain, harbors a specialized population of mitotically active neuronal progenitor cells that undergo extensive rearrangements while continuing to proliferate throughout life.

Aging↗

PubMedDate not supplied

Carving chaos: genetics and the classification of mood and psychotic syndromes.

Though Kraepelin's century-old division of major mental illness into mood disorder and schizophrenia remains in place, debate abounds over the most appropriate classification. Although these arguments previously rested solely on clinical grounds, they now are rooted in genetics and neurobiology. This article reviews evidence from the fields of genetic epidemiology, linkage, association, cytogenetics, and gene expression. Taken together, these data suggest some overlap in the genes that predispose to bipolar disorder and schizophrenia. One gene, DAOA (D-amino acid oxidase activator, also known as G72), has been repeatedly implicated as an overlap gene, while DISC1 and others may constitute additional shared susceptibility genes. Further, some evidence implicates syndromes of co-occurring mood and psychotic symptoms in association with the putative risk alleles in overlap genes. From a nosologic perspective, the existence of overlap genes, coupled with the genotype-phenotype correlations discovered to date, supports the reality of the much debated schizoaffective disorder. Potential non-overlap syndromes--such as nonpsychotic bipolar disorder or cyclothymic temperament, on the one hand, and negative symptoms or the deficit syndrome, on the other--could turn out to have their own unique genetic determinants. If genotypes are to be the anchor points of a clinically useful system of classification, they must ultimately be shown to inform prognosis, treatment, and prevention. No gene variants have yet met these tests in bipolar disorder or schizophrenia.

Bipolar Disorder↗

PubMed1978

Restoration of growth control in malignantly transformed mouse fibroblasts grown in a chemically defined medium.

The expression of growth control and morphological transformation was studied in methylcholanthrene-transformed C3H/10T 1/2 CL8 cells serially propagated in CDM by first exposing cells to albumin (0.1%) before dispersing them with trypsin (50 microgram/ml). In serum-supplemented media, methylcholanthrene-transformed C3H/10T 1/2 CL8 cells exhibit various aspects of the transformed phenotype such as irregular morphology, extensive cell overlap, lack of density-dependent inhibition of division, a saturation density of 1.1 X 10(5) cells/sq cm and tumorigenicity in vivo. Cell phenotype in CDM was dramatically altered. Methylcholanthrene-transformed C3H/10T 1/2 1/2 CL8 cells adapted to CDM exhibited a regular epithelioid morphology with no cell overlap and formed confluent monolayers of nonproliferating cells at a saturation density of 5 X 10(4) cells/sq cm. The mean generation time of logarithmic-phase cells was 25 to 27 hr. Reversion to the transformed phenotype followed addition of albumin (0.1%) or serum (2%) to logarithmic-phase cultures or exposure (30 to 60 sec) to trypsin (10 microgram/ml). Cultures in CDM reexposed to serum remained highly tumorigenic in vivo. The data suggest that absorbed proteins may block transformation-sensitive cell surface sites responsible for growth control and that these sites are inactivated by trypsin.

Albumins↗

PubMed1999

Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission.

We describe two additional instances of atelosteogenesis, type III, in a woman and her son. Clinical and radiographic information concerning these individuals allows further definition of this rare skeletal dysplasia. This is the first documentation of survival to adulthood of an individual with this disorder, of prenatal diagnostic assessment of an affected individual, and of vertical transmission suggestive of autosomal dominant inheritance. The clinical and radiologic phenotype of atelosteogenesis, type III overlaps with that of another skeletal dysplasia, autosomal dominant Larsen syndrome; these most likely represent allelic conditions.

Adult↗

PubMed1998

Genes on mouse chromosomes 2 and 9 determine variation in ethanol consumption.

Quantitative trait locus (QTL) mapping efforts in alcohol (ethanol) research are beginning to generate promising data that may ultimately lead to the identification of genes influencing alcohol addiction. Rodents have been extensively utilized to study ethanol's rewarding and aversive effects, and to demonstrate the existence of genetic influences on traits such as free-choice ethanol-consumption, ethanol-conditioned place preference and ethanol-conditioned taste aversion. The purpose of the current investigation was to verify or eliminate from further consideration putative QTLs for free-choice ethanol consumption originally identified in BXD Recombinant Inbred (RI) strains and other informative genetic crosses. B6D2F2 mice were utilized in a verification testing strategy to evaluate the viability of putative ethanol consumption QTLs. When data were combined from BXD RI, B6D2F2 and short-term selected line (STSL) mapping studies, verification was obtained for two QTLs, one on Chromosome (Chr) 9 (proximal-mid) and another on Chr 2 (distal), and suggestive verification was obtained for QTLs on Chrs 2 (proximal), 3, 4, 7, and 15. In addition, the possible genetic association of ethanol consumption with conditioned place preference was evaluated. Genetic correlations were estimated from BXD RI strain means, and QTL maps for these traits were compared to evaluate the possibility of a genetic association. The correlational analysis yielded a trend (r = 0.34, p = 0.09), but no statistically significant results. However, comparisons of QTL mapping results between phenotypes suggested some possible genetic overlap for these traits, both putative measures of ethanol reward. These data suggest that the determinants of these two measures are genetically diverse, but may share some common genetic elements.

Alcohol Drinking↗

PubMed2005

Differential detection of deletion 22q11.2 syndrome by specialty and indication.

This study identified cytogenetic abnormalities in a population screened for deletion 22q11.2 syndrome (D22S) by fluorescence in situ hybridization (FISH) and G-banding and correlated these abnormalities to referring specialty and submitted indications. Requests for the D22S FISH assay were retrospectively reviewed over a 29-month period in our institution. Positive test results for D22S FISH and other abnormalities found by other FISH assays and G-banding were correlated to submitting specialist and indication. Thirteen medical services ordered D22S FISH testing on 297 patients over 29 months. The detection rate for all cytogenetic aberrations was 9.4% (28 of 297) including 5.4% (16 of 297) for D22S detection by FISH and 2.7% (8 of 297) for detection of additional cytogenetic anomalies by G-banding cytogenetics. Sixty-six of 297 patients negative by D22S FISH and G-banding were screened using other FISH assays and 3 of 47 (6.4%) patients screened using subtelomeric probes were positive for deletion and 1 of 3 (33%) patients screened for Prader-Willi syndrome was positive for deletion. Pediatric geneticists requested 53.9% (160 of 297) of the tests, yielding 60.7% (17 of 28) of positive test results. Tetralogy of Fallot and developmental delay were the indications associated with the most positive test results. In our institution, pediatric geneticists identify the largest spectrum of indications with D22S and appear most aware of the association of developmental delay with D22S. Performing conventional cytogenetics and other FISH assays, in addition to FISH for D22S, is important because there is considerable overlap between D22S and the phenotype of several other syndromes.

Abnormalities, Multiple↗

PubMed2026

Understanding tumor adaptations and resistance to MET inhibitors in MET-altered non-small cell lung cancer.

AIM: Type Ib MET inhibitors are clinically active in selected MET-altered non-small cell lung cancer, particularly tumors with MET exon 14 skipping or MET amplification, but acquired resistance remains incompletely understood. Here, we investigated resistance across biologically distinct MET-altered contexts, including MET exon 14 skipping, MET amplification, and MET overexpression. METHODS: Paired baseline and progression samples from seven patients treated with tepotinib or capmatinib were analyzed using spatial transcriptomics, whole-exome sequencing, RNA sequencing, CRISPR screening, and drug-combination assays. Patient-derived cultures and resistant cell-line models were used to explore resistance-associated changes. RESULTS: MET inhibitor resistance was heterogeneous, with persistence of the initial MET alteration in most evaluable cases and emergence of patient-specific genomic events. Three main resistance-associated, often overlapping, routes were identified: on-target MET evolution through kinase-domain alterations; extracellular matrix and tumor-microenvironment remodeling, including collagen and fibronectin upregulation, complement-related signaling, and partial EMT-associated programs; and bypass signaling involving EGFR/HER, MAPK, and PI3K/Akt pathways. In vitro models reproduced several tumor-cell-intrinsic features but only partially captured microenvironment-associated changes. CONCLUSIONS: MET inhibitor resistance in this cohort involved overlapping, context-dependent genomic, phenotypic, and signaling adaptations, supporting combination strategies for MET-altered lung cancer.

CRISPR screen↗

PubMed2003

Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats.

Neuropathic pain models, such as the chronic constriction injury (CCI) model, are partial nerve injury models where there exist both intact and injured peripheral axons. Recent studies suggested that dorsal root ganglion (DRG) neurons with intact axons also show the alteration of excitability and gene expression and might have some role in the pathophysiological mechanisms of neuropathic pain. The incidence of pain-related behavior after the CCI is unstable and variable. In the present study, we used activating transcription factor 3 (ATF3) expression as a neuronal injury marker, and analyzed a relationship between the number of axotomized neurons and the incidence of pain-related behavior. We divided all rats into three groups according to the percentage of ATF3-immunoreactive (IR) neurons, group 1 (<12.5%), group 2 (12.5-25%), and group 3 (>25%). We found that rats in groups 2 and 3 showed thermal hyperalgesia, whereas only the rats in group 2 developed tactile allodynia from the third day to the fourteenth day after surgery. Rats in group 1 did not show thermal hyperalgesia or tactile allodynia. The DRG neurons in group 2 contained ATF3-IR neurons mainly in medium- and large-sized neurons. In order to investigate brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid(A)-receptor (GABA(A)-R) regulation in both intact and injured primary afferent neurons after the CCI, we used a double-labeling method with immunohistochemistry and in situ hybridization, as well as double immunofluorescent staining. The CCI induced an increased number of BDNF-labeled neurons in the ipsilateral DRG and the increase in BDNF expression was observed mainly in small- and medium-sized neurons that were mainly ATF3-negative. On the other hand, the number of GABA(A)-Rgamma2 subunit mRNA-positive neurons decreased in the ipsilateral DRG and GABA(A)-R- and ATF3-labeled neurons rarely overlapped. These changes in molecular phenotype in intact and injured primary afferents may be involved in the pathophysiological mechanisms of neuropathic pain produced by partial nerve injury.

Activating Transcription Factor 3↗

PubMed2004

[Childhood infections: friends or foes?].

Asthma prevalence has increased significantly; this increase appears to be relatively recent. The observed increases in this prevalence cannot be genetic in origin; on the other hand lifestyles have changed in many ways for environment or feeding. The hygiene hypothesis must be distinguished in terms whether one is addressing asthma or atopy. Although there are associations between asthma and atopy, they are not interchangeable. The pathogenic links between childhood infections and asthma require an undisputed definition of asthma. But many wheezing syndromes have been recognized in the pediatric age group, some overlap exists between these various phenotypes. The age at first severe infection seems to be crucial in determining the outcome of reinfection and suggests that the environment of the neonatal lung is a major determinant of disease and allergic patterns in later life.

Air Pollution, Indoor↗

PubMed2005

Histiocytic sarcoma: a study of five cases including the histiocyte marker CD163.

Histiocytic sarcoma (HS) is a rare but controversial hematopoietic neoplasm. In the past, malignancies have been misclassified as histiocytic tumors due to overlapping histologic features and inadequate phenotypic data. CD163, a recently characterized hemoglobin scavenger receptor, appears to be a 'specific' marker of histiocytic lineage and a promising diagnostic tool for evaluating histiocytic neoplasms. Five cases of HS were studied to further elucidate the clinicopathologic features of these rare tumors and to demonstrate the diagnostic utility of CD163. Criteria for diagnosis included histologic and immunohistochemical evidence of histiocytic differentiation, CD45 positivity, and exclusion of lymphoid, epithelial, melanocytic and dendritic cell phenotype. Sites of disease included the colon (two cases), palate, inguinal lymph node, and testis. The clinical course was aggressive in 4/5 patients (survival=2-15 months). One patient with localized disease of the palate, survived 17 years after diagnosis. All patients with poor survival had tumors > or =3.5 cm. Histologically, all cases showed diffuse architecture with large, discohesive polygonal cells. Spindling of cells was focally noted. Hemophagocytosis was identified in 3/5 cases. A prominent inflammatory background was present in 4/5 tumors. All cases were immunoreactive for CD45, CD163, CD68, and lysozyme. S-100 was focally positive in 4/5 cases. Antibodies for melanocytic, epithelial, lymphoid, and dendritic cell markers were negative. Molecular studies showed monoclonal IgH gene rearrangements in three cases. Our findings suggest that HS is an uncommon neoplasm frequently extranodal in presentation and aggressive in behavior, with rare exceptions. Stage of disease and possibly tumor size are significant prognostic indicators. Molecular studies remain controversial in the diagnosis. The morphologic and phenotypic features are relatively uniform; however, the diagnosis requires exclusion of more common neoplasms by extensive immunophenotypic studies. CD163 appears to be a specific histiocytic marker and is important in establishing the diagnosis of HS.

Adult↗

PubMed2006

The CRH family coding for cell wall glycosylphosphatidylinositol proteins with a predicted transglycosidase domain affects cell wall organization and virulence of Candida albicans.

In Candida albicans UTR2 (CSF4), CRH11, and CRH12 are members of a gene family (the CRH family) that encode glycosylphosphatidylinositol-dependent cell wall proteins with putative transglycosidase activity. Deletion of genes of this family resulted in additive sensitivity to compounds interfering with normal cell wall formation (Congo red, calcofluor white, SDS, and high Ca(2+) concentrations), suggesting that these genes contribute to cell wall organization. A triple mutant lacking UTR2, CRH11, and CRH12 produced a defective cell wall, as inferred from increased sensitivity to cell wall-degrading enzymes, decreased ability of protoplasts to regenerate a new wall, constitutive activation of Mkc1p, the mitogen-activated protein kinase of the cell wall integrity pathway, and an increased chitin content of the cell wall. Importantly, this was accompanied by a decrease in alkali-insoluble 1,3-beta-glucan but not total glucan content, suggesting that formation of the linkage between 1,3-beta-glucan and chitin might be affected. In support of this idea, localization of a Utr2p-GFP fusion protein largely coincided with areas of chitin incorporation in C. albicans. As UTR2 and CRH11 expression is regulated by calcineurin, a serine/threonine protein phosphatase involved in tolerance to antifungal drugs, cell wall morphogenesis, and virulence, this points to a possible relationship between calcineurin and the CRH family. Deletion of UTR2, CRH11, and CRH12 resulted in only a partial overlap with calcineurin-dependent phenotypes, suggesting that calcineurin has additional targets. Interestingly, cells deleted for UTR2, CRH11, and CRH12 were, like a calcineurin mutant, avirulent in a mouse model of systemic infection but retained the capacity to colonize target organs (kidneys) as the wild type. In conclusion, this work establishes the role of UTR2, CRH11, and CRH12 in cell wall organization and integrity.

Animals↗

PubMed2002

Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes.

Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central-nervous-system involvement, and arthropathy. In the present study, we report, in seven unrelated patients with CINCA syndrome, distinct missense mutations within the nucleotide-binding site of CIAS1, a gene encoding cryopyrin and previously shown to cause Muckle-Wells syndrome and familial cold urticaria. Because of the severe cartilage overgrowth observed in some patients with CINCA syndrome and the implications of polymorphonuclear cell infiltration in the cutaneous and neurological manifestations of this syndrome, the tissue-specific expression of CIAS1 was evaluated. A high level of expression of CIAS1 was found to be restricted to polymorphonuclear cells and chondrocytes. These findings demonstrate that CIAS1 missense mutations can result in distinct phenotypes with only a few overlapping symptoms and suggest that this gene may function as a potential inducer of apoptosis.

Amino Acid Sequence↗