Explore the vast range of titles available.

In patients with X-linked hypophosphatemia, which is caused by PHEX mutations and is characterized by high FGF-23 and rickets, burosumab, an FGF-23 monoclonal antibody, improved renal phosphate reabsorption, serum phosphorus levels, and linear growth and reduced rickets severity.

Endosomes have emerged as a central hub and pathogenic driver of Alzheimer’s disease (AD). The earliest brain cytopathology in neurodegeneration, occurring decades before amyloid plaques and cognitive decline, is an expansion in the size and number of endosomal compartments. The strongest genetic risk factor for sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4). Previous studies have shown that ApoE4 potentiates presymptomatic endosomal dysfunction and defective endocytic clearance of amyloid beta (Aβ), although how these two pathways are linked at a cellular and mechanistic level has been unclear. Here, we show that aberrant endosomal acidification in ApoE4 astrocytes traps the low-density lipoprotein receptor-related protein (LRP1) within intracellular compartments, leading to loss of surface expression and Aβ clearance. Pathological endosome acidification is caused by ε4 risk allele-selective down-regulation of the Na⁺/H⁺ exchanger isoform NHE6, which functions as a critical leak pathway for endosomal protons. In vivo, the NHE6 knockout (NHE6KO) mouse model showed elevated Aβ in the brain, consistent with a causal effect. Increased nuclear translocation of histone deacetylase 4 (HDAC4) in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 allele, suggested a mechanistic basis for transcriptional down-regulation of NHE6. HDAC inhibitors that restored NHE6 expression normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, and amyloid clearance. Thus, NHE6 is a downstream effector of ApoE4 and emerges as a promising therapeutic target in AD. These observations have prognostic implications for patients who have Christianson syndrome with loss of function mutations in NHE6 and exhibit prominent glial pathology and progressive hallmarks of neurodegeneration.

The obesity-associated inflammation of white adipose tissue (WAT) is one of the factors leading to the development of related diseases such as insulin resistance and liver steatosis. Recently, microRNAs (miRNAs) were identified as important regulators of WAT functions. Herein, we cultured human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes with macrophage-conditioned medium (MacCM) and performed an Affimetrix miRNA array to identify miRNAs differentially expressed under inflammatory conditions. We identified 24 miRNAs differentially expressed upon inflammation in human adipocytes and miR-146a was the most up-regulated miRNA species. In subcutaneous WAT, miR-146a was elevated in both human and murine obesity. Transfection of miR-146a mimics prevented the MacCM-induced inflammatory response in SGBS adipocytes as seen by reduced levels of IL-8 and MCP-1 mRNA and protein. We identified IRAK1 and TRAF6 as targets of miR-146a in human adipocytes and detected a reduced inflammation-induced activation of JNK and p38 upon miR-146a transfection. Taken together, we could show that miR-146a reduces the inflammatory response in human adipocytes. In a negative feedback loop miR-146a might contribute to the regulation of inflammatory processes in WAT and possibly prevent an overwhelming inflammatory response.

Mutations in the PQBP1 gene ( polyglutamine-binding protein-1 ) are responsible for a syndromic X-linked form of neurodevelopmental disorder (XL-NDD) with intellectual disability (ID), named Renpenning syndrome. PQBP1 encodes a protein involved in transcriptional and post-transcriptional regulation of gene expression. To investigate the consequences of PQBP1 loss, we used RNA interference to knock-down (KD) PQBP1 in human neural stem cells (hNSC). We observed a decrease of cell proliferation, as well as the deregulation of the expression of 58 genes, comprising genes encoding proteins associated with neurodegenerative diseases, playing a role in mRNA regulation or involved in innate immunity. We also observed an enrichment of genes involved in other forms of NDD ( CELF2, APC2 , etc). In particular, we identified an increase of a non-canonical isoform of another XL-NDD gene, UPF3B , an actor of nonsense mRNA mediated decay (NMD). This isoform encodes a shorter protein (UPF3B_S) deprived from the domains binding NMD effectors, however no notable change in NMD was observed after PQBP1 -KD in fibroblasts containing a premature termination codon. We showed that short non-canonical and long canonical UPF3B isoforms have different interactomes, suggesting they could play distinct roles. The link between PQBP1 loss and increase of UPF3B_S expression was confirmed in mRNA obtained from patients with pathogenic variants in PQBP1 , particularly pronounced for truncating variants and missense variants located in the C-terminal domain. We therefore used it as a molecular marker of Renpenning syndrome, to test the pathogenicity of variants of uncertain clinical significance identified in PQPB1 in individuals with NDD, using patient blood mRNA and HeLa cells expressing wild-type or mutant PQBP1 cDNA. We showed that these different approaches were efficient to prove a functional effect of variants in the C-terminal domain of the protein. In conclusion, our study provided information on the pathological mechanisms involved in Renpenning syndrome, but also allowed the identification of a biomarker of PQBP1 deficiency useful to test variant effect.

Key Points Functional specialization of the gene content of the X chromosome occurs in mammals: the X chromosome is highly enriched in male-specific genes (which are expressed in the testes), as well as in female-biased genes and brain-specific genes. Diverse molecular mechanisms are involved in upregulation of expressed genes on the active X chromosome to balance gene expression with the autosomes (which are present in two copies). Initiation of X chromosome inactivation (XCI) is not conserved in early development of mammalian species, which leads to early embryonic sex-specific differences before gonadal development. Genes that escape XCI show sex biases in gene expression levels. The peculiar modes of X chromosome regulation, especially mosaicism and skewing of XCI, influence the severity of diseases caused by X-linked mutations. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. This Review discusses the causes and consequences of variability in X-linked gene expression. Genes on the mammalian X chromosome are present in one copy in males and two copies in females. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. In early development, delayed and incomplete X chromosome inactivation (XCI) in some species causes variability in gene expression. Additional diversity stems from escape from XCI and from mosaicism or XCI skewing in females. This causes sex-specific differences that manifest as differential gene expression and associated phenotypes. Furthermore, the complexity and diversity of X dosage regulation affect the severity of diseases caused by X-linked mutations.

High aerobic glycolysis not only provides energy to cancer cells, but also supports their anabolic growth. JMJD1A, a histone demethylase that specifically demethylates H3K9me1/2, is overexpressed in multiple cancers, including urinary bladder cancer (UBC). It is unclear whether JMJD1A could promote cancer cell growth through enhancing glycolysis. In this study, we found that downregulation of JMJD1A decreased UBC cell proliferation, colony formation and xenograft tumor growth. Knockdown of JMJD1A inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including GLUT1, HK2, PGK1, PGM, LDHA and MCT4 . Mechanistically, JMJD1A cooperated with hypoxia inducible factor 1α (HIF1α), an important transcription factor for glucose metabolism, to induce the glycolytic gene expression. JMJD1A was recruited to the promoter of glycolytic gene PGK1 to demethylate H3K9me2. However, the JMJD1A (H1120Y) mutant, which loses the demethylase activity, failed to cooperate with HIF1α to induce the glycolytic gene expression, and failed to demethylate H3K9me2 on PGK1 promoter, suggesting that the demethylase activity of JMJD1A is essential for its coactivation function for HIF1α. Inhibition of glycolysis through knocking down HIF1α or PGK1 decelerated JMJD1A-enhanced UBC cell growth. Consistent with these results, a positive correlation between JMJD1A and several key glycolytic genes in human UBC samples was established by analyzing a microarray-based gene expression profile. In conclusion, our study demonstrates that JMJD1A promotes UBC progression by enhancing glycolysis through coactivation of HIF1α, implicating that JMJD1A is a potential molecular target for UBC treatment.

The causative mechanism for the immunodeficiency and autoinflammatory disease XLPDR is unknown. Burstein and colleagues show that XLPDR is caused by disruption of POLA1 , which encodes a DNA polymerase subunit; this, in turn, leads to dysregulated production of type I interferons. Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1 , which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

Transcription and mRNA processing are tightly coupled regulatory layers on gene expression, and their perturbations underly human disorders. X-linked Dystonia-Parkinsonism (XDP) is a unique example of a human disease connecting aberrant mRNA processing and the basal transcription machinery. XDP is a rare, monogenic fatal neurodegenerative disorder, and a limited understanding of the underlying molecular mechanisms hinders the development of effective therapies. In this study, we show that depletion of BRD4, a chromatin reader known for its role in transcriptional pausing, rescues the XDP molecular signature. Unexpectedly, this effect is independent of the canonical coactivator role of BRD4. We demonstrate that the XDP-SVA induces intronic premature cleavage and polyadenylation within the TAF1 locus, and that BRD4 depletion bypasses this premature termination checkpoint. These findings reveal new dimensions of BRD4 activity beyond transcription pause release and suggest modulation of mRNA processing as a therapeutic strategy for XDP. X‑linked dystonia‑parkinsonism involves disrupted transcription and mRNA processing. Here, the authors show that altering 3′ mRNA processing rescues the disease molecular signature, linking XDP pathology to a non‑canonical function of the transcriptional regulator BRD4.

Background Creatine Transporter Deficiency (CTD) is a rare X-linked disorder caused by pathogenic or likely pathogenic variants in the SLC6A8 gene, leading to a deficiency of cerebral Creatine. Clinically, CTD manifests as a complex neurodevelopmental disorder and is associated with Intellectual Disability (ID), language and socio-communicative impairments, behavioral challenges and, often, epilepsy. Methods This study was conducted in two phases: (i) An eSurvey was distributed among major Italian clinics specializing in rare neurometabolic diseases to create a national census of CTD patients, with extensive clinical data; (ii) A retrospective observational study was performed on patients who had undergone regular long-term follow-up using a consistent neuropsychological assessment and treatment protocol. Results We identified 18 CTD male patients, aged 18 months to 32 years at diagnosis. Within this cohort, 3 to 13 years follow-up clinical information was collected for 10 patients. A specific clinical protocol was applied to this subgroup, where a biochemical or 1 H-MRS diagnosis was confirmed in 8 patients (urine Creatine/Creatinine ratio > 1), while in the remaining 2 patients, genetic testing was diagnostic and neurochemical tests followed. 1 H-MRS consistently showed a decreased Creatine peak in all patients. All 10 patients exhibited ID with significant speech disorder, and 6 had epilepsy. The treatment protocol for this cohort involved oral Arginine supplementation. Conclusions Diagnosing CTD remains clinically challenging due to the often negative results from a first tier clinical diagnostic test for intellectual disability (ID) (i.e. family history, cytogenetic testing and Fragile X) and neuroimaging without spectroscopy. CTD should be carefully considered when investigating severe ID with autistic-like traits and significant speech impairment, with or without epilepsy. The Urine Creatine/Creatinine ratio assay is a quick initial diagnostic step, which can be corroborated by a brain MRI/ 1 H-MRS and molecular genetics. Even considering previouis literature findings, it is not yet possible, to demonstrate definite genotype-phenotype correlations, although a milder functional impairment has been suggested for missense SLC6A8 pathogenic or likely pathogenic variants. Treatment strategies supplementation with Creatine and its precursors have provided heterogeneous and inconsistent results. Recently proposed innovative therapeutic strategies such as lipophilic Creatine analogs and betaine supplementation in animal models need validation in human disease.

Eric Vilain and colleagues identify missense mutations in the imprinted gene CDKN1C , encoding the p57KIP2 cyclin dependent kinase inhibitor, in individuals with IMAGe syndrome. IMAGe syndrome is a developmental disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies. IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences 1 . An identity-by-descent analysis in a family with IMAGe syndrome 2 identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C (also known as P57KIP2 ) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression 3 , and we found that targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C , suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding, distinguishing them from the mutations of CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome 4 .