Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “X-linked”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed2024

Fabry disease in female monozygotic twins with complex intronic haplotype variants: a case report.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disease caused by the impairment of α-galactosidase A. The complex intronic haplotype (CIH) variants, located in promoter and intronic regulatory lesions, has been found in patients with classical forms of Fabry disease. We present a case of Fabry disease in female monozygotic twins exhibiting the CIH mutation and classical manifestations. CASE PRESENTATION: A 61-year-old woman with a history of stroke, carotid artery occlusion, hypertrophic cardiomyopathy, and chronic kidney disease was referred to the nephrology clinic for management of her chronic kidney disease. Her monozygotic twin sister also presented with hypertrophic cardiomyopathy, atrial flutter, carotid stenosis, and proteinuria. Clinical symptoms and a comprehensive family history strongly suggested the presence of Fabry disease. Genetic analysis revealed the presence of 5 variants within a complex intronic haplotype (CIH): c.-10 C > T, c.369 + 990 C > A, c.370 - 81_370-77delCAGCC, c.640-16 A > G, and c.1000-22 C > T. We conducted a review of the patient's previous kidney biopsy findings, which demonstrated the presence of lamellated inclusion bodies in electron microscopy. Remarkably, both the monozygotic twin sister and her son exhibited the same genetic mutation. Enzyme replacement therapy was initiated for the patient. Her kidney function decreased throughout a thorough 2-year follow-up period, while there was a slight decrease in the left ventricular mass index. CONCLUSIONS: This is the first reported case of female monozygotic twins with the CIH variants representing cardiac, cerebrovascular, and renal manifestations suggestive of Fabry disease.

Humans↗
PubMed2022

Current advances in gene therapy of mitochondrial diseases.

Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders.

Humans↗
PubMed2026

Sex and tissue resolved co-expression networks reveal a female placental-brain axis protective against prenatal PCB exposure.

BACKGROUND: Neurodevelopmental disorders have a strong male bias that is poorly understood. The placenta provides molecular information about environmental interactions with genetics (including biological sex) that shape developmental processes in the brain. We investigate placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). RESULTS: To understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta RNAseq data, we use weighted gene correlation network analysis (WGCNA) to create gene networks that could be compared across sex or tissue. WGCNA reveals that expression within most correlated gene networks is significantly and strongly associated with PCB exposure, but frequently in opposite directions between male-female and placenta-brain comparisons. In WGCNA and differentially expressed gene analyses, more transcriptional changes are observed in male brain than placenta, but the reverse is seen in females. Furthermore, female X-inactive specific transcript (Xist) levels correlate with sex-specific and non-monotonic PCB dose response, suggesting an X-linked protective epigenetic mechanism. The transcriptomic effects of low-dose PCB exposure are significantly opposed by dietary folic acid supplementation across both sexes but are strongest in female placentas. PCB and folic acid interacting gene networks are enriched in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipid, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. CONCLUSIONS: A female protective effect in response to prenatal PCB exposure appears to be mediated by dose-dependent sex differences in transcriptional modulation of placental metabolic pathways.

Female↗
PubMed2026

Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.

BACKGROUND: Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders. METHODS: We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076). RESULTS: Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions. CONCLUSIONS: CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.

BCLAF3↗
PubMed2026

Duchenne muscular dystrophy: from gene to gene-ius therapies.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional dystrophin, leading to progressive muscle degeneration, loss of ambulation, respiratory failure, cardiomyopathy, and premature mortality. Despite advances in multidisciplinary supportive care, DMD remains an incurable disease associated with substantial physical, psychosocial, and economic burdens. The monogenic nature of DMD and its well-defined molecular pathogenesis have made it a prime target for the development of precision therapies aimed at restoring dystrophin expression or modifying disease progression. This review provides an overview of the genetic and molecular mechanisms underlying DMD, summarizes its clinical manifestations and natural history, and discusses current standards of care. It further examines recent advances in disease-modifying therapeutic strategies, including exon-skipping antisense oligonucleotides, nonsense mutation readthrough agents, adeno-associated virus (AAV)-mediated micro-dystrophin gene replacement, and emerging genome-editing technologies such as CRISPR/Cas9. The review also highlights the limitations of existing treatments, including mutation specificity, variable efficacy, immune-related challenges, and uncertainties regarding long-term durability and safety. Finally, it considers future directions in therapeutic development, emphasizing the need for combination approaches, improved delivery systems, and next-generation gene-editing platforms to achieve more effective and lasting clinical outcomes. Collectively, these advances represent a paradigm shift in DMD management and offer renewed hope for improving survival and quality of life for affected individuals.

Humans↗
PubMed2026

RNA sequencing resolves a novel noncanonical splice-region variant in PHKA2 causing glycogen storage disease type IX α2: a case report.

BACKGROUND: Glycogen storage disease type IX α2 (GSD IX α2) is an X-linked hepatic glycogenosis caused by pathogenic variants in PHKA2. Noncanonical splice-region variants located outside the invariant GT/AG dinucleotides pose significant interpretive challenges, as in silico predictions alone are often insufficient for definitive classification. CASE DESCRIPTION: We report a 2.9-year-old boy presenting with short stature, hepatomegaly, markedly elevated aminotransferases, fasting hypoglycemia with ketonuria, hypercholesterolemia, coagulation parameter abnormalities (decreased fibrinogen and prolonged thrombin time), and histological evidence of early hepatic fibrosis as demonstrated by Masson's trichrome staining (portal fibrosis and perisinusoidal fibrosis). Whole-exome sequencing (WES) identified a hemizygous, previously unreported PHKA2 variant [NM_000292.3:c.2517+5G>T, genomic location (GRCh38): NC_000023.11: g.18907895G>T], initially classified as a variant of uncertain significance (VUS) under American College of Medical Genetics and Genomics (ACMG) criteria. RNA sequencing of peripheral blood leukocytes demonstrated predominant exon 22 skipping in 94.2% of informative junction reads, predicting a frameshift and premature termination codon [p.(Gly788Profs*74)] with predicted loss of the C-terminal CBL 2 subdomain. Incorporating this transcript-level evidence, the variant was reclassified as pathogenic (PVS1 + PM2_Supporting + PP4). Following dietary management with uncooked cornstarch supplementation, the patient showed progressive biochemical improvement over a 2.2-year follow-up. CONCLUSIONS: This case expands the mutational spectrum of PHKA2 and demonstrates that RNA sequencing of accessible tissues is a practical and diagnostically informative strategy for resolving noncanonical splice-region variants in pediatric hepatic GSD. Early hepatic fibrosis detected by histological examination before age 3 years underscores the importance of longitudinal hepatic surveillance in GSD IX α2.

Glycogen storage disease type IX α2 (GSD IX ↗
PubMed2026

Xp21 contiguous gene deletion syndrome presenting as congenital adrenal hypoplasia: molecular diagnosis and clinical re-evaluation of a pedigree.

OBJECTIVE: To investigate the molecular etiology in a male child clinically suspected of congenital adrenal hyperplasia (CAH) with negative conventional genetic testing, and to elucidate the genetic characteristics of his pedigree. METHODS: Clinical data from the proband and his family members were collected. Molecular diagnostics proceeded sequentially: initial targeted CAH testing (CYP21A2 and POR sequencing/MLPA, plus targeted NR0B1 CNV analysis) was followed by whole-exome sequencing coupled with genome-wide CNV analysis. RESULTS: The proband presented with neonatal cyanosis and hyperpigmentation. Laboratory tests showed markedly elevated ACTH (354.68 pmol/L) and low aldosterone (57.24 pg/mL). Molecular genetic testing identified a hemizygous deletion of approximately 4.44 Mb at Xp21.3-p21.1 (chrX:g.27080000_31520000), encompassing the NR0B1, GK, IL1RAPL1, and DMD genes. CNV-seq confirmed that the mother carried a heterozygous deletion of 4.38 Mb in the same region, while the father and four maternal aunts showed normal genotypes. CONCLUSION: This study ultimately diagnosed the proband with Xp21 contiguous gene deletion syndrome. The adrenal insufficiency resulted from X-linked congenital adrenal hypoplasia (AHC) due to NR0B1 haploinsufficiency, rather than CAH. These findings highlight the considerable clinical overlap between AHC and CAH, indicating that CNV analysis of the Xp21 region should be included in the diagnostic workup for male infants with suspected CAH but negative routine genetic testing. This provides a basis for the precise diagnosis and genetic counseling of such patients.

Humans↗
PubMed2026

A novel hemizygous missense variant in the BEND2 gene is associated with nonobstructive azoospermia.

Nonobstructive azoospermia (NOA), the most severe form of male infertility, frequently arises from genetic defects that disrupt spermatogenesis. In this study, a novel hemizygous missense variant (NM_001184767.2 [c.G1069A; p.V357I]) is identified in the X-linked BEN domain-containing 2 ( BEND2 ) gene of a patient with NOA characterized by spermatocyte maturation arrest. Whole-exome sequencing and Sanger validation confirmed that this rare variant is absent in fertile controls and that no pathogenic variants were detected in established NOA genes. Computational analysis predicted potential structural alterations via AlphaFold modeling, leading to the hypothesis that the ability of BEND2 to recognize genomic targets may be compromised. The patient's phenotype phenocopies the meiotic arrest observed in Bend2 -knockout mice. Expression profiling confirmed predominant BEND2 transcription in human and mouse testes, peaking in early spermatocytes and coinciding with meiotic initiation, with reduced transcript levels detected in the proband's peripheral blood compared with those in an obstructive azoospermia control. This study reports a pathogenic BEND2 variant associated with NOA with spermatocyte arrest, highlighting its critical role in human meiosis and expanding the genetic etiology of male infertility.

Adult↗
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↗
PubMed1977

Sensitive, optimized assay for serum AMP deaminase.

A sensitive, optimized assay for serum AMP deaminase (EC 3.5.4.6) is presented, which is based on a colorimetric indophenol determination of ammonia liberated during the enzyme reaction. An average enzyme activity in serum of 2.7 U/liter (n = 36, range 0-6.2) for healthy adults was established. Both the enzyme and colorimetric reactions were optimized to give an assay sensitivity of 0.2 U/liter of serum, a 98-99% analytical recovery in the normal serum enzyme concentration range, and a CV of 7.9% in-run and 10.6% between-run. This optimization included studies on specific buffer, pH, ionic strength, and potential activators. The Km for the enzyme in serum was determinated to be 1.4 X 10(-3) mol/liter, which agrees well with the value reported for human skeletal muscle enzyme. Above-normal serum AMP deaminase activity may be present in various myopathies and could be useful in detecting carriers of the X-linked dystrophies.

AMP Deaminase↗
PubMedDate not supplied

[Contribution of biology to nosology of depressive states. Neurochemical, endocrine and genetic factors (author's transl)].

Genetic factors have been evidenced in the etiology of manic-depressive syndromes through twins, morbidity risk studies, linkage studies with genetic markers such as color blindness and the Xga blood group, as well as through adoption studies. Most genetic studies indicate that there is a genetic and biological heterogeneity in manic-depressive illness. Among these manic-depressive syndromes, one group is consistent with a dominant X-linked transmission of the disease. From the neurochemical point of view, most investigators emphasize the importance of cerebral neurotransmitter substances such as catecholamines and indolamines in the pathogenesis of bipolar depressive states. According with this hypothesis, depression is associated with a functional deficit in brain monoamines while mania may be due to an hyperproduction of monoamines. These neuropharmacological studies are of importance because they also have neuroendocrine implications. Some pituitary hormones are secreted under the control of brain monoamines, and they are also implicated in the pathogenesis of depressive states.

Bipolar Disorder↗
PubMed1975

B lymphocytes lacking surface IG in patients with immune deficiency: initiation of IG synthesis in culture in cells of a patient with thymoma.

A 64-year-old woman with a syndrome of thymoma, severe hypogammaglobulinemia, seemingly normal cell-mediated immunity and aplastic anemia, was found to have virtually no immunoglobulin- (Ig) bearing peripheral blood lymphocytes (PBL). However, 7.8 +/- 3.4% of the PBL were positive for another B-cell marker, the receptor for aggregated IgG, while the remaining cells bound sheep erythrocytes. Those cells which were aggregate-reactive appeared to be immature or incomplete B cells. Cultures of peripheral blood leukocytes from the patient in various serum-containing media were studied by 3 independent technics for the development of lymphocyte surface Ig and for Ig in the culture supernatants. In vitro the patient's cells were able to develop surface Ig in media supplemented with fetal calf serum (FCS) or normal serum; in media supplemented with autologous serum, the cells developed no surface Ig. During the cultures in FCS, human Ig determinants became detectable in the medium, and both medium and cell-surface Ig underwent a shift from mu determinants early in the culture period to gamma and alpha determinants later. The development of Ig on the cells was not inhibited by the presence of autologous serum if FCS was included in the medium. These data support the concept that a factor, missing from this patient's serum, is required at an early stage in the maturation of the B cell. A patient with X-linked agammaglobulinemia had a population of circulating lymphocytes with surface characteristics similar to the B cells of the thymoma case. In contrast, no Ig synthesis by this patient's cultured cells could be demonstrated, indicating a different level of block in the 2 cases despite their similarity at the level of the cell surface.

Agammaglobulinemia↗
PubMed1975

On the diagnosis of Fabry's disease.

Fabry's disease is a recessive X-linked inborn error of metabolism due to deficiency of the lysosomal enzyme alpha-galactosidase. The large variety of symptoms may make the diagnosis difficult. A severely afflicted female patient is presented. For several years she had been treated under the diagnosis polyarteritis nodosa until the characteristic cutaneous lesions of Fabry's disease were recognized. Enzymatic studies and electronmicroscopic examinations confirmed the diagnosis. A symptomatic effect of corticosteroid treatment was proven. The grave prognosis, the recent attempts at enzyme substitution therapy and the possibility of preventing new cases by prenatal diagnosis should stimulate the efforts of the clinician to diagnose the disease.

Adult↗
PubMed1976

Peripheral blood T and B cell characteristics in a patient with severe combined immune deficiency (SCID) maintained in a gnotobiotic environment.

Peripheral blood lymphocytes obtained at 24-30 months after birth from a male with X-linked severe combined immune deficiency maintained in a gnotobiotic environment were characterized by T and B cell surface markers. A high proportion (55-80 percent) of circulating lymphocytes bore surface IgM as detected by direct immunofluorescence. A receptor for the activated C3 complement component was detected on 27-47 percent of his lymphocytes. Only 4-12 percent of the peripheral blood lymphocytes formed spontaneous rosettes with sheep erythrocytes (E-R). In general, no blastogenesis was detected in lymphocyte cultures stimulated with pokeweed mitogen or phytohemagglutinin although transient slightly positive responses to both mitogens were occasionally observed. Incubation of lymphocytes with bovine thymosin Fraction V did not increase the percentage of E-R nor induce lymphocyte blastogenesis in the presence of phytohemagglutinin.

B-Lymphocytes↗
PubMed1975

[First experiences with amniocentesis from genetic indications].

Genetically indicated amniocentesis was performed in 93 patients in the first half of pregnancy and in 36 in the second half. To the common and recognized indications several obstetric indications were added. Six (4.7%) fetal abnormalities were diagnosed by karyotyping and determination of alpha1-fetoprotein (AFP), i.e. a child with trisomy 21 and a boy with XXY Klinefelter syndrome, both in mothers aged over 40, a partial trisomy 3 in a pregnancy with a balanced anomaly, 2 boys with X-linked hereditary disease and an anencephalic. In 4 cases (3.1) abortion was performed at the parents' request. Three pregnancies ended in spontaneous abortion. In 54 cases in which amniocentesis was performed in the first half of pregnancy the babies have now been born. One was found to have a congenital heart defect and the remainder were healthy. In the cases which had undergone genetic screening during the second half of pregnancy 3 neonates displayed anomalies not detectable by karyotyping or AFP determination, one of which was hydrocephalus. The abortion rate was 0.8%.

Anencephaly↗
PubMed1976

Prenatal diagnosis of genetic disease in Canada: report of a collaborative study.

A study of 1223 amniocenteses carried out during 1020 pregnancies in 990 women showed that 2nd-trimester amniocentesis at about 16 weeks' gestation is a safe, accurate and reliable procedure for the diagnosis of certain classes of genetic disease when it is monitored by ultrasound, performed by a trained obstetrician and carried out in a major health sciences centre. The percentage of fetal losses (4.7%) and neonatal deaths (0.5%) during the study was not greater than in control samples for women 35 years of age and older. The best results were obtained when needles of gauge 20 or 21 were used. The use of needles of gauge 19 or larger and more than two insertions during a single amniocentesis were associated with a significantly greater frequency of fetal loss than a second or even a third amniocentesis during the same pregnancy. For 39 fetuses (3.8%) a diagnosis of a genetic abnormality was made and 23 male fetuses were found to be potentially hemizygous for an X-linked gene. There were 51 therapeutic abortions as a result of the diagnosis. Sixty-six tests (5.4%) gave an inconclusive result and seven (0.6%) gave an erroneous diagnosis; five of the latter (two false-positives and three false-negatives) resulted from the alpha1-fetoprotein test for neural-tube defects and in two cases the sex was incorrectly determined. The frequency of all chromosome abnormalities was 1:20 when the mother's age was 40 years or more and 1:60 when the mother's age was between 35 and 39 years. When a mother had previously had a child with a chromosome abnormality the risk of recurrence of such an abnormality was 1:100 when the age of the mother was 35 years or more.

Abortion, Therapeutic↗
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↗