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Journal of Cellular and Molecular... Dec 2023More and more attention is paid to diseases such as internal transfer and brain malformation which are caused by the abnormal morphogenesis of cilia. These cilia-related... (Review)
Review
More and more attention is paid to diseases such as internal transfer and brain malformation which are caused by the abnormal morphogenesis of cilia. These cilia-related diseases are divided into two categories: ciliopathy resulting from defects of primary cilia and primary ciliary dyskinesia (PCD) caused by functional dysregulation of motile cilia. Cilia are widely distributed, and their related diseases can cover many human organs and tissues. Recent studies prove that primary cilia play a key role in maintaining homeostasis in the cardiovascular system. However, molecular mechanisms of cilia-related diseases remain elusive. Here, we reviewed recent research progresses on characteristics, molecular mechanisms and treatment methods of ciliopathy and PCD. Our review is beneficial to the further research on the pathogenesis and treatment strategies of cilia-related diseases.
Topics: Humans; Cilia; Ciliary Motility Disorders; Ciliopathies; Mutation
PubMed: 37830491
DOI: 10.1111/jcmm.17990 -
Brain : a Journal of Neurology Aug 2023In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later...
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Topics: Male; Humans; Cross-Sectional Studies; Mutation; Phenotype; Dystonia; Dystonic Disorders; Nervous System Malformations; Molecular Chaperones
PubMed: 36757831
DOI: 10.1093/brain/awad039 -
Cell Dec 2023Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a...
Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.
Topics: Humans; Fragile X Syndrome; Trinucleotide Repeat Expansion; DNA Methylation; Mutation; Fragile X Mental Retardation Protein
PubMed: 38134876
DOI: 10.1016/j.cell.2023.11.019 -
Cells Sep 2023The premutation of the fragile X messenger ribonucleoprotein 1 () gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5'... (Review)
Review
The premutation of the fragile X messenger ribonucleoprotein 1 () gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.
Topics: Humans; Fragile X Mental Retardation Protein; Mutation; RNA, Messenger; Trinucleotide Repeat Expansion; Fragile X Syndrome
PubMed: 37759552
DOI: 10.3390/cells12182330 -
JAMA Neurology Sep 2023Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and...
IMPORTANCE
Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.
OBJECTIVE
To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations.
DESIGN, SETTING, AND PARTICIPANTS
This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control.
MAIN OUTCOMES AND MEASURES
The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed.
RESULTS
In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families.
CONCLUSIONS AND RELEVANCE
This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.
Topics: Humans; Polymicrogyria; Exome Sequencing; Retrospective Studies; Mutation, Missense; Siblings; Nerve Tissue Proteins; Connexins
PubMed: 37486637
DOI: 10.1001/jamaneurol.2023.2363 -
Italian Journal of Dermatology and... Aug 2023Rubinstein-Taybi Syndrome is a rare congenital multisystem syndrome inherited in an autosomal dominant pattern caused by mutations in CREBBP and EP300 genes in... (Review)
Review
Rubinstein-Taybi Syndrome is a rare congenital multisystem syndrome inherited in an autosomal dominant pattern caused by mutations in CREBBP and EP300 genes in approximately 60% and 10% respectively. These genes encode two highly evolutionarily conserved, ubiquitously expressed, and homologous lysine-acetyltransferases, that are involved in number of basic cellular activities, such as DNA repair, cell proliferation, growth, differentiation, apoptosis of cells, and tumor suppression. It is mainly characterized by global developmental delay, moderate to severe intellectual disability, postnatal retardation, microcephaly, skeletal anomalies including broad/short, angled thumbs and/or large first toes, short stature, and dysmorphic facial features. There is an increased risk to develop tumors mainly meningiomas and pilomatrixomas, without a clear genotype-phenotype correlation. Although not considered as characteristic manifestations, numerous cutaneous anomalies have also been reported in patients with this entity. Both susceptibility to the formation of keloids and pilomatricomas are the most often associated cutaneous features. In this review, we discuss the genetics, diagnosis, and clinical features in Rubinstein-Taybi Syndrome with a review of the major dermatological manifestations.
Topics: Humans; Rubinstein-Taybi Syndrome; Mutation; Intellectual Disability; Genetic Association Studies; Pilomatrixoma; Skin Neoplasms
PubMed: 37282850
DOI: 10.23736/S2784-8671.23.07547-3 -
The Journal of Clinical Investigation Apr 2024Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%-2% of newborns. Patients with a CM localized on the... (Review)
Review
Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%-2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene (GNAQ) encoding guanine nucleotide-binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.
Topics: Infant, Newborn; Animals; Humans; Glaucoma; Models, Animal; Mutation; Capillaries; Vascular Malformations
PubMed: 38618955
DOI: 10.1172/JCI172842 -
Blood Advances Aug 2023TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional...
TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance.
Topics: Humans; Chromothripsis; Mutation; Chromosome Aberrations; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Myelodysplastic Syndromes; Genomics; Tumor Suppressor Protein p53
PubMed: 37339484
DOI: 10.1182/bloodadvances.2023010156 -
Chromosome Research : An International... Aug 2023Mistakes in chromosome segregation leading to aneuploidy are the primary cause of miscarriages in humans. Excluding sex chromosomes, viable aneuploidies in humans... (Review)
Review
Mistakes in chromosome segregation leading to aneuploidy are the primary cause of miscarriages in humans. Excluding sex chromosomes, viable aneuploidies in humans include trisomies of chromosomes 21, 18, or 13, which cause Down, Edwards, or Patau syndromes, respectively. While individuals with trisomy 18 or 13 die soon after birth, people with Down syndrome live to adulthood but have intellectual disabilities and are prone to multiple diseases. At the cellular level, mistakes in the segregation of a single chromosome leading to a cell losing a chromosome are lethal. In contrast, the cell that gains a chromosome can survive. Several studies support the hypothesis that gaining an extra copy of a chromosome causes gene-specific phenotypes and phenotypes independent of the identity of the genes encoded within that chromosome. The latter, referred to as aneuploidy-associated phenotypes, are the focus of this review. Among the conserved aneuploidy-associated phenotypes observed in yeast and human cells are lower viability, increased gene expression, increased protein synthesis and turnover, abnormal nuclear morphology, and altered metabolism. Notably, abnormal nuclear morphology of aneuploid cells is associated with increased metabolic demand for de novo synthesis of sphingolipids. These findings reveal important insights into the possible pathological role of aneuploidy in Down syndrome. Despite the adverse effects on cell physiology, aneuploidy is a hallmark of cancer cells. Understanding how aneuploidy affects cell physiology can reveal insights into the selective pressure that aneuploid cancer cells must overcome to support unlimited proliferation.
Topics: Humans; Down Syndrome; Sex Chromosomes; Aneuploidy; Trisomy; Chromosome Segregation
PubMed: 37620607
DOI: 10.1007/s10577-023-09732-w -
Tidsskrift For Den Norske Laegeforening... Mar 2024Anemia in children is common and finding the underlying cause is often uncomplicated. However, in some cases, the underlying diagnosis is rare and difficult to diagnose.
BACKGROUND
Anemia in children is common and finding the underlying cause is often uncomplicated. However, in some cases, the underlying diagnosis is rare and difficult to diagnose.
CASE PRESENTATION
A toddler presented with severe anemia with normal red cell indices and a low reticulocyte count. The remaining hematological parameters were normal, bar a slight thrombocytosis. At this point a diagnosis of transient erythroblastopenia of childhood (TEC) was made. The child continued to have slight anemia with intermittent macrocytosis and reticulocytopenia throughout childhood. Growth and development was normal, and there were no signs of congenital abnormalities in the heart or kidneys nor any craniofacial or phalangeal defects. Repeated bone marrow examinations showed no significant abnormal findings. As a teenager the patient was diagnosed with Diamond-Blackfan anemia through an exome-based gene panel which revealed a mutation in the RPL11 gene.
INTERPRETATION
Congenital bone marrow failure syndromes do not always present in the classical way, leading to a delayed diagnosis. The increasing availability of different gene panels for patients with persistent abnormal hematological laboratory parameters offers the possibility of a more accurate diagnostic pathway, which is important for adequate follow-up and genetic counselling.
Topics: Adolescent; Humans; Anemia; Anemia, Diamond-Blackfan; Anemia, Hemolytic, Congenital; Mutation
PubMed: 38506013
DOI: 10.4045/tidsskr.23.0415