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At least 109 records · Page 6Linked to original sources
PubMed2026

Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function.

The X-linked G-protein coupled receptor GPR174 is highly expressed in T and B lymphocytes and has immunoregulatory roles in mice, but its function in humans is unknown. We describe a cohort of six individuals who have function-disrupting variants in GPR174 and a clinical phenotype of lymphadenopathy and autoimmunity. Histological analysis of two patient lymph nodes revealed necrotizing lymphadenitis and lymphoproliferation resembling Kikuchi-Fujimoto disease. In-depth analysis of three patients and related carriers revealed overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (TEMRA). Patient cells and GPR174-deficient CD8 T cells generated from controls showed less repression of proliferation by the GPR174 ligand lysophosphatidylserine (lysoPS) and an effector-biased gene expression program. GPR174-deficient CD4 T cells were resistant to lysoPS-mediated suppression of IL2 production. In mice, chronic viral infection led to over-accumulation of GPR174-deficient effector CD8 T cells. We describe an inborn error of immunity associated with dysregulated lymphocyte responses that we propose predisposes to exaggerated lymphoproliferation and autoimmunity following viral infection.

Journal Article↗
PubMed1978

Induction of human immunoglobulin synthesis and secretion in somatic cell hybrids of mouse myeloma and human B lymphocytes from patients with agammaglobulinemia.

Somatic cell hybrid clones were isolated from the fusion of RPC 5,4 mouse myeloma cells and B lymphocytes from three patients with agammaglobulinemia. One patient had X-linked agammaglobulinemia; the remaining two patients had common varied agammaglobulinemia. All three patients had B lymphocytes which fail to secrete immunoglobulin. The hybrid nature of the clones was established by examination of metaphase chromosome spreads. Most of the clones from all three patients expressed surface immunoglobulin of mouse and human parental origin. Clones from two of the patients had fewer cells with surface Ig than hybrids from normal persons, while clones from the third patient had large numbers of surface Ig fluorescent cells. Most of the clones from all three patients synthesized and secreted human and mouse immunoglobulin. As determined by sodium dodecyl sulfate acrylamide gel electrophoresis of radioactively labeled proteins, clones from each of the patients produced human gamma, alpha, and mu-heavy chains. These studies demonstrate the presence of functional structural genes coding for human immunoglobulin heavy chains in B lymphocytes of patients with agammaglobulinemia. Further, they represent induction in the somatic cell hybrids of a gene product not expressed in the parental B lymphocytes.

Agammaglobulinemia↗
PubMed1975

Heredity in primary endocardial fibroelastosis.

Twenty-six cases of endocardial fibroelastosis were collected from three hospitals in Manchester over a ten-year period. Nine cases occurred in 4 families and these are discussed in detail. X-linked recessive inheritance seems likely in one family in which two probable female carriers had subarachnoid haemorrhages. In a second family an apparently normal man produced two children with endocardial fibroelastosis by different mothers suggesting autosomal dominant inheritance with incomplete penetrance. Autosomal recessive inheritance may be involved in the remaining two families but this was not associated with consanguinity. Genetic heterogeneity is evident in endocardial fibroelastosis and the majority of cases occur sporadically. An accurate family history is therefore necessary but it is difficult to give precise recurrence risks in sporadic cases.

Cardiomegaly↗
PubMed1978

X-linked recessive (Duchenne) muscular dystrophy (DMD) and purine metabolism: effects of oral allopurinol and adenylate.

Data are presented which suggest that Duchenne muscular dystrophy (DMD) may have some origin in a severe deficiency of total muscle adenine nucleotides. Using double-blind techniques, this possibility was tested in 16 DMD patients by giving oral allopurinol, a synthetic inhibitor of the purine catabolic enzyme xanthine oxidase. Sublingual procaine adenylate was also briefly tested. Instances of clinical improvement quickly occurred which were statistically significant; they were accompanied by a significant increase in physical strength. These improvements have been maintained for more than 6 mo by administration of a small amount of allopurinol daily. Procaine adenylate had little effect. These results support the above view of DMD and seem to indicate that existing purines, retained and recycled after allopurinol, can sustain such improvement, and that additional adenylate is unnecessary.

Adenosine Monophosphate↗
PubMed1979

Effects of N-nitrosopiperidine substitutions on mutagenicity in Drosophila melanogaster.

N-Nitrosopiperidine (NP) and various derivatives were fed to Drosophila melanogaster males over a wide concentration range in order to assess their mutagenic potency in the induction of X-linked recessive lethals and chromosome loss. NP was effective in inducing lethals, as were its halogen and methyl-substituted derivatives, with the exception of 2,6-dimethyl NP. (Methyl substitutions at the alpha carbon atoms reduce or eliminate mutagenic activity.) Substitution of halogen groups on the piperidine ring enhanced the mutagenic activity, with the 3-chloro compound being the most mutagenic. In contrast, substitutions with a hydroxyl, carboxyl, or keto group resulted in a loss of mutagenicity. None of the compounds tested increased the frequency of chromosome loss or breakage in mature sperm.

Animals↗
PubMed2026

EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.

IMPORTANCE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches. OBJECTIVE: To describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically. EXPOSURES: Complete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES). MAIN OUTCOMES AND MEASURES: The main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis. RESULTS: The series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina. CONCLUSION AND RELEVANCE: This case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.

Adolescent↗
PubMed2026

ATRX Condensates as Candidate Organizers of Enhancer-Centered Nuclear Microenvironments in Neural Progenitors: A Hypothesis for Enhancer-Associated ATRX Function in Neural Progenitors.

Neural progenitor cells (NPCs) must preserve lineage identity while remaining responsive to developmental cues. Here, we discuss the hypothesis that ATRX condensates help organize enhancer-centered nuclear microenvironments in NPCs. ATRX has long been studied in heterochromatin maintenance, histone variant deposition, and chromatin remodeling; earlier work has also shown that ATRX can occupy euchromatic and active regulatory regions and contribute to transcriptional regulation. Recent evidence in human NPCs indicates that ATRX forms nuclear puncta with condensate-like properties, associates with neurogenic enhancer-rich regions, and incorporates regulatory factors such as CHD7 and p300. Perturbation of ATRX condensate formation is associated with changes in enhancer-associated ATRX occupancy, neural gene-expression programs, and neuroepithelial organization, suggesting a regulatory mode that may complement canonical heterochromatin-associated functions. We propose a dual-mode model in which folded domains contribute to chromatin anchoring at repressive regions, whereas intrinsically disordered regions support condensate-associated organization at active developmental enhancers. We emphasize that whether ATRX condensates activate enhancers de novo, stabilize pre-existing enhancer states, buffer transcriptional variability, or primarily organize cofactor localization remains unresolved. We also discuss limitations of the current evidence and outline acute, locus-specific experiments needed to test the model.

X-linked Nuclear Protein↗
PubMed1977

Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome.

Investigation of a family with cancer in boys revealed that at least 20 males had the X-linked recessive lymphoproliferative syndrome. A variety of phenotypes occurred: aproliferative phenotypes consisted of aplastic anemia, agranulocytosis or acquired hypogammaglobulinemia; and proliferative phenotypes of B cells included disorders associated with the Epstein-Barr virus, American Burkitt's lymphoma, immunoblastic sarcoma of B cells, fatal infectious mononucleosis or plasmacytoma. The lymphoproliferative disorders observed in males could have resulted from an immunodeficiency to Epstein-Barr virus. The variable phenotypic expression could have resulted from individual differences in the viral dose, duration of exposure and age at which the boys were exposed to the virus. Aproliferative phenotypes such as acquired hypogammaglobulinemia could have ensued from excessive suppressor-cell activity on B cells, whereas proliferative phenotypes such as Burkitt's lymphoma or fatal infectious mononucleosis could have resulted from infection by Epstein-Barr virus and failure to stop proliferation of B cells.

Adolescent↗
PubMed2024

Comparative genomic landscape of lower-grade glioma and glioblastoma.

Biomarkers for classifying and grading gliomas have been extensively explored, whereas populations in public databases were mostly Western/European. Based on public databases cannot accurately represent Chinese population. To identify molecular characteristics associated with clinical outcomes of lower-grade glioma (LGG) and glioblastoma (GBM) in the Chinese population, we performed whole-exome sequencing (WES) in 16 LGG and 35 GBM tumor tissues. TP53 (36/51), TERT (31/51), ATRX (16/51), EFGLAM (14/51), and IDH1 (13/51) were the most common genes harboring mutations. IDH1 mutation (c.G395A; p.R132H) was significantly enriched in LGG, whereas PCDHGA10 mutation (c.A265G; p.I89V) in GBM. IDH1-wildtype and PCDHGA10 mutation were significantly related to poor prognosis. IDH1 is an important biomarker in gliomas, whereas PCDHGA10 mutation has not been reported to correlate with gliomas. Different copy number variations (CNVs) and oncogenic signaling pathways were identified between LGG and GBM. Differential genomic landscapes between LGG and GBM were revealed in the Chinese population, and PCDHGA10, for the first time, was identified as the prognostic factor of gliomas. Our results might provide a basis for molecular classification and identification of diagnostic biomarkers and even potential therapeutic targets for gliomas.

Humans↗
PubMed1978

Cell culture of individual Drosophila embryos. II. Culture of X-linked embryonic lethals.

Results are reported from the culturing in vitro of cells from individual early gastrulae of the following four groups of X-linked embryonic lethal mutants of Drosophila melanogaster. (1) Notch lethals, Five Notch mutants were studied which have been reported to give similar abnormalities in whole embryos: the nervous system displays a three-fold hypertrophy as part of a shift in the pattern of differentiation within ectodermal derivatives, and mesodermal derivatives do not differentiate. An hypertrophy of nerve was found in cell cultures prepared from embryos of all five mutants. In addition, four of the five alleles consistently gave abnormalities of muscle differentiation: when compared to controls, Notch cultures had a reduced frequency of myotubes, and displayed unusual clusters of myocytes which had either failed to fuse or had fused incompletely. Results from mixed cultures prepared from two embryos were consistent with the autonomous expression of nerve and muscle abnormalities by Notch-8 cells in the presence of wild-type cells. It is argued that the Notch locus has a direct role in the differentiation of both nerve and muscle. (2) white deficiencies. Cells carrying either of two deficiencies gave a clear-cut pattern of abnormalities: initial cellular differentiations were normal, but nerve, muscle and fat-body cells progressively deteriorated during the culture period. Mixed cultures showed that wild-type cells could not 'rescue' mutant muscle and fat-body cells; however, the status of the autonomy of mutant nerve abnormalities in these cultures was unclear. Both white deficiencies remove cytological band 3C1, and this permits a comparison of results with those from cultures of cells from Notch-8 embryos (also deficient for 3C1). Abnormalities displayed in cultures of the two types of mutant show no overlap. Therefore no consistent cellular abnormality can be attributed to absence of band 3C1. (3) lethal(1)myospheroid. In contrast to earlier observations on in vitro cell cultures (Donady & Seecof, 1972) muscle was seen to differentiate, though its morphology was extremely abnormal. Observations indicated that all cell types within the cultures had poor properties of adhesion to a glass substrate. It is argued that the observed abnormalities are not consistent with a mutant lesion which is restricted to the basement membrane (contra Wright, 1960), and that all cell types carry a basic defect which may reside in the cell membrane. (4) shibirets alleles. Cultures of two temperature-sensitive lethal shibire alleles (shits1), shits3) were normal at the permissive temperature of 22 degrees C. At the restrictive temperature (29 degrees C) early cell differentiation was normal but subsequent development was blocked. This blockage could be partially reversed by shifting cultures to the permissive temperature after as much as 10 days exposure to the high temperature. It is suggested that shits cells are mutant in a process which is basic to several cell types.

Animals↗
PubMed1976

Mutagen sensitivity of Drosophila melanogaster. III. X-linked loci governing sensitivity to methyl methanesulfonate.

Twenty-eight X-linked, recessive mutations of Drosophila melanogaster conferring enhanced sensitivity to the monofunctional alkylating agent, methyl methanesulfonate, have been recoered and assigned to five complementation groups. These groups can be distinguished on the basis of map location and variations in the pattern of mutagen sensitivity. Allelism of members of one complementation group with the previously described meiotic mutant, mei-41, (Baker and Carpenter, 1972) as well as the frequent appearance of female infertility with mutagen sensitivity suggests associated defects in meiotic chromosome behavior or early embryogenesis. Examination of the mutagen sensitivity of double mutants has led to the formulation of a working model of DNA repair for this organism. Studies of a similar nature (Boyd et al., 1976) have identified five additional X chromosome complementation groups, suggesting that the genome of Drosophila melanogaster may contain many loci involved with mutagen sensitivity. The continued isolation and characterization of conditional mutants of this type promises future insights into the mechanisms of DNA replication, DNA repair and recombination in this complex higher eucaryote.

Animals↗
PubMed1976

Human gene mapping using an X/autosome translocation.

Human fibroblasts containing a translocation between the X chromosome and chromosome 15 were fused with the 6-thioguanine-resistant mouse cell line, IR. Resulting hybrids, selected in HAT medium, retained the X/15 chromosome. Hybrids which were counterselected in 6-thioguanine lost this chromosome. The X-linked markers glucose-6-phosphate dehydrogenase (G6PD), phosphoglycerate kinase (PGK), and hypoxanthine phosphoribosyl transferase (HPRT), and the non-X-linked markers pyruvate kinase (PKM2) mannose phosphate isomerase (MPI), N-acetyl hexosaminidase A (HEXA) and beta2-microglubulin (beta2-m) all segregated in concordance with the X/15 translocation chromosome. The latter markers have been assigned to chromosome 15. Selection against the X/15 chromosome was done using antihuman beta2-m serum. Electrophoretic and immunochemical analyses of the N-acetyl hexosaminidases A and B in these hybrids were performed.

Acetylglucosaminidase↗
PubMed2026

Epigenetic aging and autosomal methylation remodeling in Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by marked clinical heterogeneity and incompletely understood genotype-phenotype correlations. While X-chromosome inactivation has been extensively investigated, the contribution of autosomal epigenetic mechanisms to phenotypic variability remains poorly defined. Here, we performed an exploratory genome-wide DNA methylation analysis in 32 AFD patients (22 females and 10 males; mean age 51.7 years) recruited within a multicenter regional research project in Calabria (Italy). DNA methylation profiling was conducted using the Infinium MethylationEPIC v2.0 array. The analysis integrated two complementary approaches: differential methylation analysis and evaluation of biological aging through multiple epigenetic clocks, including Horvath, Hannum, PhenoAge, Skin & Blood, GrimAge, and DunedinPACE. Exploratory methylome-wide analysis identified a limited set of CpG loci showing nominal evidence of methylation differences between carriers of pathogenic and non-pathogenic variants; however, none remained statistically significant after correction for multiple testing. Annotation of the top-ranking nominal CpG associations highlighted genes involved in biological processes including vascular regulation, intracellular trafficking, cytoskeletal organization, immune signaling, and lipid metabolism. No significant differences between groups were observed for the conventional epigenetic age-acceleration measures examined. In contrast, carriers of pathogenic variants showed significantly higher DunedinPACE values (p = 0.0328), indicating a faster estimated pace of biological aging. This finding suggests that DunedinPACE may capture aspects of the cumulative systemic burden associated with pathogenic GLA variants, although confirmation in larger independent cohorts is required. Overall, this pilot epigenomic study provides preliminary evidence that autosomal epigenetic remodeling and biological aging acceleration may contribute to phenotypic heterogeneity in AFD.

Anderson-Fabry disease↗
PubMed2026

Two iPSC lines with frameshift mutations in FTSJ1 as models for X-linked non-syndromic intellectual disability.

CRISPR/Cas9 was used to introduce two different FTSJ1 frameshift mutations into an existing human male iPSC line (UMGWi004-B). No additional genomic or chromosomal changes were detected. The modified iPSC express different stem cell markers and can be induced to differentiate into cells from all three germ layers. FTSJ1 is ubiquitously expressed and mutations in this X-chromosomal gene are involved in an intellectual developmental disorder (OMIM: #309549). These cells can be used to model the disease at the cellular and organoid level in their original state or after differentiation into cell types of interest.

Journal Article↗
PubMed1978

Epstein-Barr virus infections in the X-linked recessive lymphoproliferative syndrome.

Prospective studies demonstrated variable phenotypic expression of the X-linked recessive lymphoproliferative syndrome (X.L.R.L.S.) in three brothers: (1) hypogammaglobulinaemia and subclinical Epstein-Barr-virus (E.B.V.) infection with antibody response to E.B.V.; (2) E.B.V. infection with defective immune response to E.B.V., fatal infectious mononucleosis (I.M.), and immunoblastic lymphoma; and (3) histiocytic lymphoma. Hypogammaglobulinaemia and measles pneumonitis had preceded infection with E.B.V. The diverse phenotypic expressions probably resulted from the varied immune response to E.B.V. Recombination of X chromosomes was documented by Xg-blood-group studies in a survivor. E.B.V. can induce fatal I.M. and malignant lymphoma in X.L.R.L.S., but an immune response to E.B.V. can be protective.

Adolescent↗
PubMed1979

Antigenic marker on a functional subpopulation of B cells, controlled by the I-A subregion of the H-2 complex.

CBA/N mice have an X-linked recessive effect that results in the absence of a subpopulation of B cells carrying the Lyb3 surface marker. It has been shown previously that this marker is present on a mature subset of B cells in all mouse strains. In this paper the Lyb3+ B cell population in C57BL/6 mice was analyzed further. This subset of B cells selectively expresses a surface marker controlled by the I-A subregion of the H-2 complex. A cytotoxic antiserum recognizing this marker was raised by immunizing defective (CBA/N X C57BL/6)F1 male mice with C57BL/6 spleen cells. This antiserum also contained noncytotoxic, non-strain-restricted anti-Lyb3 antibodies. The possible functional relevance of this surface marker is discussed.

Animals↗
PubMed1976

Isolation and characterization of X-linked mutants of Drosophila melanogaster which are sensitive to mutagens.

Thirteen X-linked mutants have been isolated in Drosophila melanogaster which render male and homozygous female larvae sensitive to the mutagen methyl methanesulfonate. Their characterization and preliminary assignment to functional groups is described. Four of these mutants are alleles of mei-41 (Baker and Carpenter 1972). Like previously isolated alleles of this locus, these mutants reduce fertility and increase loss and nondisjunction of the X-chromosome in homozygous females. The remaining mutants have been tentatively assigned to six functional groups (two mutants to the mus(1)101 locus, two to mus(1)102 , two to mus(1)103, and one each to mus(1)104, mus(1)105 , and mus(1)106). Several of the complementation groups can be distinguished on the basis of nondisjunction and cross sensitivity to mutagens. Females homozygous for the mei-41, mus(1)101 and mus(1)102 mutants exhibit elevated levels of nondisjunction. Mutants belonging to complementation groups mei-41, mus(1)101, and mus(1)104 are sensitive to nitrogen mustard (HN2) in addition to their MMS sensitivity. Among these mutants there is currently a direct correlation between sensitivity to HN2, sensitivity to 2-acetylaminofluorene and a deficiency in post-replication repair ( Boyd and Setlow 1976). Only the mei-41 mutants are hypersensitive to UV radiation, although several of the mutants exhibit sensitivity to gamma-rays. Semidominance is observed in female larvae of the mei-41, mus(1)104, and mus(1)103 mutants after exposure to high concentrations of MMS. The properties of the mutants generally conform to a pattern which has been established for related mutants in yeast. Additional properties of these mutants are summarized in Table 9.

Alleles↗
PubMed1979

Regional localization of the gene for human phosphoribosylpyrophosphate synthetase on the X chromosome.

Sixty-eight independent hybrid clones were isolated after irradiated normal human lymphocytes were fused with Chinese hamster fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase activity. The cells were grown under selective conditions requiring retention of the X chromosome-linked locus for human hypoxanthine-guanine phosphoribosyltransferase. The frequency and patterns of cotransference of human phosphoribosylpyrophosphate synthetase with the selected marker and with additional X-linked enzymatic markers confirm X linkage of the structural gene for human phosphoribosylpyrophosphate synthetase and support assignment of this gene to a position on the long arm of the X, between the loci for alpha-galactosidase and hypoxanthine-guanine phosphoribosyltransferase.

Chromosome Mapping↗