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Journal of Neurodevelopmental Disorders Feb 2024X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous... (Review)
Review
X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous expression of X-linked genes in females. This is because most genes on the X chromosome are subject to random X chromosome inactivation (XCI) during early embryonic development, which results in a mosaic pattern of gene expression for a given X-linked mutant allele. This mosaic expression produces substantial complexity, especially when attempting to study the already complicated neural circuits that underly behavior, thus impeding the understanding of disease-related pathophysiology and the development of therapeutics. Here, we review a few selected X-linked forms of ID that predominantly affect heterozygous females and the current obstacles for developing effective therapies for such disorders. We also propose a genetic strategy to overcome the complexity presented by mosaicism in heterozygous females and highlight specific tools for studying synaptic and circuit mechanisms, many of which could be shared across multiple forms of intellectual disability.
Topics: Female; Humans; Pregnancy; Chromosomes, Human, X; Genes, X-Linked; Intellectual Disability; Mosaicism; X Chromosome Inactivation
PubMed: 38424476
DOI: 10.1186/s11689-024-09517-0 -
The Journal of International Medical... Feb 2024Philadelphia chromosome-positive (Ph+) T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive type of acute leukemia. The Philadelphia chromosome is the...
Philadelphia chromosome-positive (Ph+) T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive type of acute leukemia. The Philadelphia chromosome is the hallmark of chronic myeloid leukemia (CML). The differentiation between Ph+ T-ALL and T-cell lymphoblastic crisis of CML may be problematic in some cases. Here, we report a rare case of de novo Ph+ T-ALL that presented a diagnostic challenge. The overall clinical, immunophenotypic, cytogenetic, and xenotransplantation results suggest a diagnosis of Ph+ T-ALL. The patient was treated with induction chemotherapy including imatinib followed by haploidentical stem cell transplantation and achieved complete remission.
Topics: Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 38422030
DOI: 10.1177/03000605231156757 -
EBioMedicine Mar 2024Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm....
BACKGROUND
Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, a growing body of evidence supports a strong genetic contribution. Recent genome-wide association study (GWAS) efforts have reported 53 independent signals associated with CTS. While GWAS can identify genetic loci conferring risk, it does not determine which cell types drive the genetic aetiology of the trait, which variants are "causal" at a given signal, and which effector genes correspond to these non-coding variants. These obstacles limit interpretation of potential disease mechanisms.
METHODS
We analysed CTS GWAS findings in the context of chromatin conformation between gene promoters and accessible chromatin regions across cellular models of bone, skeletal muscle, adipocytes and neurons. We identified proxy variants in high LD with the lead CTS sentinel SNPs residing in promoter connected open chromatin in the skeletal muscle and bone contexts.
FINDINGS
We detected significant enrichment for heritability in skeletal muscle myotubes, as well as a weaker correlation in human mesenchymal stem cell-derived osteoblasts. In myotubes, our approach implicated 117 genes contacting 60 proxy variants corresponding to 20 of the 53 GWAS signals. In the osteoblast context we implicated 30 genes contacting 24 proxy variants coinciding with 12 signals, of which 19 genes shared. We subsequently prioritized BZW2 as a candidate effector gene in CTS and implicated it as novel gene that perturbs myocyte differentiation in vitro.
INTERPRETATION
Taken together our results suggest that the CTS genetic component influences the size, integrity, and organization of multiple tissues surrounding the carpal tunnel, in particular muscle and bone, to predispose the nerve to being compressed in this disease setting.
FUNDING
This work was supported by NIH Grant UM1 DK126194 (SFAG and WY), R01AG072705 (SFAG & KDH) and the Center for Spatial and Functional Genomics at CHOP (SFAG & ADW). SFAG is supported by the Daniel B. Burke Endowed Chair for Diabetes Research. WY is supported by the Perelman School of Medicine of the University of Pennsylvania.
Topics: Humans; Carpal Tunnel Syndrome; Genome-Wide Association Study; Muscle, Skeletal; Chromosome Mapping; Chromatin; DNA-Binding Proteins
PubMed: 38417377
DOI: 10.1016/j.ebiom.2024.105038 -
Genes Feb 2024While the manifestations of many inherited retinal disorders are limited to loss of vision, others are part of a syndrome that affects multiple tissues, particularly the...
While the manifestations of many inherited retinal disorders are limited to loss of vision, others are part of a syndrome that affects multiple tissues, particularly the nervous system. Most syndromic retinal disorders are thought to be recessively inherited. Two dogs out of a litter of Cirneco dell' Etna dogs, both males, showed signs of retinal degeneration, along with tremors and signs described as either atypical seizures or paroxysmal dyskinesias, while the other two male littermates were normal. We named this oculo-neurological syndrome CONS (Cirneco oculo-neurological syndrome), and undertook homozygosity mapping and whole-genome sequencing to determine its potential genetic etiology. Notably, we detected a 1-bp deletion in chromosome 6 that was predicted to cause a frameshift and premature stop codon within the canine gene, which encodes adenosine monophosphate deaminase, an enzyme that converts adenosine 5'-monophosphate (AMP) to inosine 5'-monophosphate (IMP). Genotyping of the available Cirneco population suggested perfect segregation between cases and controls for the variant. Moreover, this variant was absent in canine genomic databases comprised of thousands of unaffected dogs. The genetic variant we identified in dogs presents with retinal manifestations, adding to the spectrum of neurological manifestations associated with variants in humans.
Topics: Animals; Dogs; Male; AMP Deaminase; Frameshift Mutation; Retina; Retinal Degeneration; Tremor; Whole Genome Sequencing
PubMed: 38397227
DOI: 10.3390/genes15020238 -
Genes Feb 2024Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome and distinct BCR::ABL1 gene transcripts. We assessed the frequencies of these transcripts... (Meta-Analysis)
Meta-Analysis
Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome and distinct BCR::ABL1 gene transcripts. We assessed the frequencies of these transcripts in Mexico, Latin America, and worldwide. We determined the prevalence of BCR::ABL1 transcripts in CML patients and intercontinental or regional variations using specialized databases and keywords. We analyzed 34 studies from 20 countries, encompassing 5795 patients. Keyword-based searches in specialized databases guided data collection. ANOVA was employed for transcript distribution analysis. The transcript was most prevalent globally, followed by , with being the least frequent. Interestingly, Mexico City exhibited a higher incidence of , while predominated in the remaining country. Overall, no significant intercontinental or regional variations were observed. was the most common BCR::ABL1 transcript worldwide, with following closely; was infrequent. Notably, this trend remained consistent in Mexico. Evaluating transcript frequencies holds clinical relevance for CML management. Understanding the frequency of transcript informs personalized CML treatments.
Topics: Humans; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Mexico
PubMed: 38397221
DOI: 10.3390/genes15020232 -
Hematology, Transfusion and Cell Therapy Feb 2024T315I mutations of the BCR::ABL1 gene lead to resistance to tyrosine kinase inhibitors (TKIs). This study evaluated the performance of digital droplet polymerase chain...
BACKGROUND
T315I mutations of the BCR::ABL1 gene lead to resistance to tyrosine kinase inhibitors (TKIs). This study evaluated the performance of digital droplet polymerase chain reaction (ddPCR) in quantifying T315I mutations and their frequency in Philadelphia chromosome (Ph) positive hematological patients.
METHODS
The course of disease and BCR::ABL1 fusion transcripts (e13a2, e14a2 and e1a2) were retrospectively reviewed in 21 patients with acute lymphoblastic leukemia (ALL) and 85 patients with chronic myeloid leukemia (CML). T315I mutation analysis was carried out using ddPCR and the limit of detection was assessed using mutant T315I DNA at varying variant allele fractions.
RESULTS
T315I mutations were found in two ALL patients and one CML patient without remission in molecular biology and with mutation burdens of 29.20%, 40.85%, and 3.00%, respectively. The mutation burden of ALL patients was higher than that of CML patients, but there was no significant difference between the two (p-value = 0.0536). The test's limit of detection was 0.02% with a correlation coefficient greater than 0.99 between the expected and actual detection abundances.
CONCLUSION
T315I mutations have a high incidence in Ph-positive ALL patients even if the course of disease is short. In molecular biology, T315I mutation detection is indicated for CML patients not in remission.
PubMed: 38383224
DOI: 10.1016/j.htct.2023.12.007 -
Molecular Microbiology May 2024The site-specific recombination pathway of bacteriophage λ encompasses isoenergetic but highly directional and tightly regulated integrative and excisive reactions that... (Review)
Review
The site-specific recombination pathway of bacteriophage λ encompasses isoenergetic but highly directional and tightly regulated integrative and excisive reactions that integrate and excise the vial chromosome into and out of the bacterial chromosome. The reactions require 240 bp of phage DNA and 21 bp of bacterial DNA comprising 16 protein binding sites that are differentially used in each pathway by the phage-encoded Int and Xis proteins and the host-encoded integration host factor and factor for inversion stimulation proteins. Structures of higher-order protein-DNA complexes of the four-way Holliday junction recombination intermediates provided clarifying insights into the mechanisms, directionality, and regulation of these two pathways, which are tightly linked to the physiology of the bacterial host cell. Here we review our current understanding of the mechanisms responsible for regulating and executing λ site-specific recombination, with an emphasis on key studies completed over the last decade.
Topics: Bacteriophage lambda; Recombination, Genetic; DNA, Viral; Viral Proteins; DNA, Bacterial; Binding Sites; Integration Host Factors
PubMed: 38372210
DOI: 10.1111/mmi.15241 -
MicroPublication Biology 2024Sleep is ancient and genetically conserved across phylogeny. Neuropeptide signaling plays a fundamental role in the regulation of sleep for mammals, fish, and...
Sleep is ancient and genetically conserved across phylogeny. Neuropeptide signaling plays a fundamental role in the regulation of sleep for mammals, fish, and invertebrates like . Developmentally timed-sleep and stress-induced sleep of are controlled by distinct and overlapping neuropeptide pathways. The RPamide neuropeptides , , and , play antagonistic roles during the regulation of developmentally-timed sleep, however, their role in stress-induced sleep has not been explored. These genes are linked on the X chromosome, which has made genetic analyses challenging. Here we used CRISPR to generate new alleles of and , ; double mutants, and ; ; triple mutants. Confirming previous studies, we find that is required for developmentally-timed sleep, and show that is also required. However, all three genes are dispensable for stress-induced sleep.
PubMed: 38371321
DOI: 10.17912/micropub.biology.001109 -
Cornea Apr 2024The International Committee for the Classification of Corneal Dystrophies (IC3D) was created in 2005 to develop a new classification system integrating current...
PURPOSE
The International Committee for the Classification of Corneal Dystrophies (IC3D) was created in 2005 to develop a new classification system integrating current information on phenotype, histopathology, and genetic analysis. This update is the third edition of the IC3D nomenclature.
METHODS
Peer-reviewed publications from 2014 to 2023 were evaluated. The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy [from category 1 (most evidence) to category 4 (least evidence)].
RESULTS
Epithelial recurrent erosion dystrophies now include epithelial recurrent erosion dystrophy, category 1 ( COL17A1 mutations, chromosome 10). Signs and symptoms are similar to Franceschetti corneal dystrophy, dystrophia Smolandiensis, and dystrophia Helsinglandica, category 4. Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19). Classic lattice corneal dystrophy (LCD) results from TGFBI R124C mutation. The LCD variant group has over 80 dystrophies with non-R124C TGFBI mutations, amyloid deposition, and often similar phenotypes to classic LCD. We propose a new nomenclature for specific LCD pathogenic variants by appending the mutation using 1-letter amino acid abbreviations to LCD. Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10). Typically asymptomatic, it can be distinguished phenotypically from pre-Descemet corneal dystrophy, category 4. We include a corneal dystrophy management table.
CONCLUSIONS
The IC3D third edition provides a current summary of corneal dystrophy information. The article is available online at https://corneasociety.org/publications/ic3d .
Topics: Humans; Corneal Dystrophies, Hereditary; Mutation; Transforming Growth Factor beta; Epithelium, Corneal; Phenotype; Extracellular Matrix Proteins; Pedigree; DNA Mutational Analysis
PubMed: 38359414
DOI: 10.1097/ICO.0000000000003420 -
Leukemia Research Reports 2024An 82-year-old man with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) complicated by hepatocarcinoma was presented. Remission induction therapy of...
An 82-year-old man with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) complicated by hepatocarcinoma was presented. Remission induction therapy of hyper-CVAD with half dose reduction achieved hematological complete remission (CR), but accompanied with elevated alanine aminotransferase and hyperbilirubinemia. The patient was thought intolerable for hyper-CVAD with half dose reduction due to liver toxicity, and treatment was switched to blinatumomab. Hematological CR was sustained after nine cycles of blinatumomab without exacerbation of liver dysfunction. After five courses of blinatumomab, hepatocarcinoma was treated successfully by trans-arterial chemoembolization. Two years after the diagnosis of ALL, the patient was alive in CR status of ALL.
PubMed: 38348414
DOI: 10.1016/j.lrr.2024.100413