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Journal of Clinical Research in... Jul 2024Most cases associated with Hereditary Severe Insulin Resistance Syndrome (H-SIRS) are linked to mutations in the insulin receptor () gene. Patients with H-SIRS typically...
Most cases associated with Hereditary Severe Insulin Resistance Syndrome (H-SIRS) are linked to mutations in the insulin receptor () gene. Patients with H-SIRS typically manifest symptoms of hyperinsulinemia, insulin resistance, and diabetes mellitus. Other symptoms include impaired glucose regulation, hyperandrogenism, and the presence of acanthosis nigricans (AN). In this report, we present two cases of H-SIRS in female children exhibiting various symptoms, such as hyperinsulinemia, fasting hypoglycemia, postprandial hyperglycemia, overweight, fatty liver, hyperandrogenism, and varying degrees of AN. One patient also presented with mental retardation. Gene sequencing identified specific mutations in the gene for both patients: c.2663A > G (p.Tyr888Cys) and c.38_61del (p.Pro13_Ala20del). These mutations have the potential to disrupt the interaction between and insulin, leading to abnormal insulin signaling, insulin resistance, and various clinical manifestations.
PubMed: 38952179
DOI: 10.4274/jcrpe.galenos.2024.2024-2-14 -
BMC Pregnancy and Childbirth Jul 2024TBX6, a member of the T-box gene family, encodes the transcription factor box 6 that is critical for somite segmentation in vertebrates. It is known that the compound...
BACKGROUND
TBX6, a member of the T-box gene family, encodes the transcription factor box 6 that is critical for somite segmentation in vertebrates. It is known that the compound heterozygosity of disruptive variants in trans with a common hypomorphic risk haplotype (T-C-A) in the TBX6 gene contribute to 10% of congenital scoliosis (CS) cases. The deletion of chromosome 17q12 is a rare cytogenetic abnormality, which often leads to renal cysts and diabetes mellitus. However, the affected individuals often exhibit clinical heterogeneity and incomplete penetrance.
METHODS
We here present a Chinese fetus who was shown to have CS by ultrasound examination at 17 weeks of gestation. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the fetus. In vitro functional experiments, including western-blotting and luciferase transactivation assay, were performed to determine the pathogenicity of the novel variant of TBX6.
RESULTS
WES revealed the fetus harbored a compound heterozygous variant of c.338_340del (p.Ile113del) and the common hypomorphic risk haplotype of the TBX6 gene. In vitro functional study showed the p.Ile113del variant had no impact on TBX6 expression, but almost led to complete loss of its transcriptional activity. In addition, we identified a 1.85 Mb deletion on 17q12 region in the fetus and the mother. Though there is currently no clinical phenotype associated with this copy number variation in the fetus, it can explain multiple renal cysts in the pregnant woman.
CONCLUSIONS
This study is the first to report a Chinese fetus with a single amino acid deletion variant and a T-C-A haplotype of TBX6. The clinical heterogeneity of 17q12 microdeletion poses significant challenges for prenatal genetic counseling. Our results once again suggest the complexity of prenatal genetic diagnosis.
Topics: Humans; T-Box Domain Proteins; Female; Chromosomes, Human, Pair 17; Haplotypes; Pregnancy; Heterozygote; Adult; Chromosome Deletion; Exome Sequencing; Sequence Deletion; Fetus; Ultrasonography, Prenatal
PubMed: 38951757
DOI: 10.1186/s12884-024-06653-2 -
Nature Communications Jul 2024The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental...
The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11 zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCF mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCF mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.
Topics: CCCTC-Binding Factor; Humans; Animals; Mice; Neurodevelopmental Disorders; Organoids; Mutation; GABAergic Neurons; Male; Chromatin; Female; Brain; Point Mutation; Human Embryonic Stem Cells
PubMed: 38951485
DOI: 10.1038/s41467-024-49684-1 -
Acta Neurologica Belgica Jul 2024Early onset ataxias (EOAs) are a heterogeneous group of rare neurological disorders that not only involve the central and peripheral nervous system but also involve... (Review)
Review
Early onset ataxias (EOAs) are a heterogeneous group of rare neurological disorders that not only involve the central and peripheral nervous system but also involve other organs. They are mainly manifested by degeneration or abnormal development of the cerebellum occurring before the age of 25 years and typically the pattern of inheritance is autosomal recessive.The diagnosis of autosomal recessive cerebellar ataxias (ARCAs) is confirmed by the clinical, laboratory, electrophysiological examination, neuroimaging findings, and mutation analysis when the causative gene is detected. Correct diagnosis is crucial for appropriate genetic counseling, estimating the prognosis, and, in some cases, pharmacological intervention. The wide variety of genotypes with a heterogeneous phenotypic manifestation makes the diagnostic work-up challenging, time-consuming, and expensive, not only for the clinician but also for the children and their parents. In this review, we focused on the step-by-step approach in which cerebellar ataxia is a prominent sign. We also outline the most common disorders in ataxias with early-onset manifestations.
PubMed: 38951452
DOI: 10.1007/s13760-024-02595-w -
Zhonghua Nei Ke Za Zhi Jul 2024To summarize the clinical, imaging, and pathological characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) to...
To summarize the clinical, imaging, and pathological characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) to improve the diagnosis of this rare disease. A retrospective case series was conducted to collect the clinical data and results of genetic testing, muscle biopsy, and imaging studies including computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS) of 35 patients with MELAS admitted to the Nanjing Drum Tower Hospital from 2012 to 2021. Descriptive statistical analysis including mean, standard deviation, and frequency percentage were carried out. The average age of onset of the patients was 30.2±2.3 years; the prevalence of family history was 20%. The two main initial symptoms were limb weakness and convulsions. The clinical manifestations of the neuromuscular system were proximal muscle weakness and exercise intolerance. The endocrine system is the most affected outside the neuromuscular system, with diabetes being the most common condition. Among the five patients who underwent brain CT, four showed hypodense lesions and two had calcified lesions. Brain MRI in 26 patients showed that the lesions more often affected the parietal lobe, basal ganglia, temporal lobe, occipital lobe, and frontal lobe than the infratentorial areas. Twelve of these individuals exhibited different levels of brain atrophy. Among the 10 patients who underwent H-MRS, nine showed a decrease in N-acetylaspartate (NAA) levels, eight exhibited abnormal lactate elevation (Lac peaks), whereas six had both reduced NAA levels and the presence of Lac peaks. Thirty-one patients underwent genetic testing; among them, 25 were found to have the mt.3243A>G mutation, while the remaining six exhibited rare gene alterations. Muscle biopsies were performed in 21 patients, and 15 showed abnormal mitochondrial proliferation manifested by ragged red fibers and defective oxidative phosphorylation manifested by cytochrome C oxidase (COX) enzyme-deficient muscle fibers. The clinical manifestations of MELAS syndrome are variable and complex, and early atypical symptoms could be missed or misdiagnosed. A detailed clinical history, imaging MRS analysis, muscle biopsy, and genetic testing are necessary to confirm the accurate diagnosis of MELAS.
Topics: Humans; MELAS Syndrome; Retrospective Studies; Adult; Magnetic Resonance Imaging; Brain; Tomography, X-Ray Computed; Male; Female; Magnetic Resonance Spectroscopy
PubMed: 38951091
DOI: 10.3760/cma.j.cn112138-20231227-00411 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2024Myeloid neoplasms (MNs) belong to a group of hematological malignancies characterized by the abnormal biological functions of hematopoietic stem progenitor cells. The...
Myeloid neoplasms (MNs) belong to a group of hematological malignancies characterized by the abnormal biological functions of hematopoietic stem progenitor cells. The abnormal immune and hematopoietic microenvironment of patients with MN interact with malignant clonal hematopoietic stem cells, promoting the occurrence and development of their diseases. MN large granular lymphocyte proliferation (MN-LGLP) is a special and rare clinical phenomenon in this type of disease. Currently, research on this disease in domestic and international cohorts is limited. This study analyzes the clinical and laboratory characteristics of this type of patient and explores the impact of LGLP on the clinical characteristics and survival of patients with MN. Patients with MN-LGLP are prone to neutropenia and splenomegaly. The presence of LGLP is not a risk factor affecting the survival of patients with MN-LGLP. STAG, ASXL1, and TET2 are the most common accompanying gene mutations in MN-LGLP, and patients with MN-LGLP and STAG2 mutations have poor prognoses.
Topics: Humans; Male; Prognosis; Female; Mutation; Middle Aged; Cell Proliferation; Adult; Aged; Leukemia, Large Granular Lymphocytic
PubMed: 38951070
DOI: 10.3760/cma.j.cn121090-20231219-00327 -
Journal of Thrombosis and Haemostasis :... Jun 2024; Factor (F)V is pivotal in both procoagulant and anticoagulant mechanisms. The present report describes a novel F5 mutation in a FV-deficient patient (FV:C 6 IU/dL,...
BACKGROUND
; Factor (F)V is pivotal in both procoagulant and anticoagulant mechanisms. The present report describes a novel F5 mutation in a FV-deficient patient (FV:C 6 IU/dL, FV:Ag 32 IU/dL), complicated with recurrent deep vein thrombosis. The patient demonstrated activated protein C resistance (APCR) with compound heterozygous mutations consisting of FV-Y1961C (FV) and FV-1982_1983del. AIM;: To clarify thrombotic mechanisms associated with this FV abnormality.
METHODS AND RESULTS
Levels of FV-1982_1983del were below the detection sensitivity in our expression experiments using HEK293T cells, and analyses were targeted, therefore on the FV-Y1961C mutation. APTT-based clotting assays demonstrated that FV-Y1961C exhibited APCR, and that the reduced APC susceptibility in FVa-Y1961C resulted in a marked depression of APC-catalyzed inactivation with delayed cleavage at Arg and little cleavage at Arg with or without protein (P)S. The APC cofactor activity of FV-Y1961C in APC-catalyzed FVIIIa inactivation promoted by Arg cleavage in FVIII was impaired. The binding affinity of FVa-Y1961C to phospholipid membranes was reduced in reactions involving APC/PS-catalyzed inactivation and in prothrombinase activity. Furthermore, the addition of FVa-Y1961C to plasma failed to inhibit tissue factor (TF)-induced procoagulant function. These characteristics were similar to those of FV-W1920R (FV) and FV-A2086D (FV).
CONCLUSIONS
; We identified a compound heterozygous. FV-Y1961C mutation in the C1 domain representing a novel FV mutation (FV) resulting in not only APCR due to impaired FVa susceptibility and FV cofactor activity for APC function, but impaired inhibition of TF-induced procoagulant function. These defects in anticoagulant function associated with FV in FV-Y1961C contributed to a prothrombotic state.
PubMed: 38950780
DOI: 10.1016/j.jtha.2024.06.014 -
The Journal of Clinical Investigation Jun 2024Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for...
Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.
Topics: Humans; Iron-Sulfur Proteins; Male; Female; Neuromuscular Diseases; Child; Cell Nucleus; Cytoplasm; Metallochaperones
PubMed: 38950322
DOI: 10.1172/JCI179559 -
The Journal of Clinical Investigation Jun 2024Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the...
Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.
Topics: Humans; Animals; Cardiomyopathy, Dilated; Mice; Myocytes, Cardiac; Mice, Knockout; Frameshift Mutation; Organoids; Male; Female; Myocardial Contraction; Adult; Disease Models, Animal
PubMed: 38950288
DOI: 10.1172/JCI177172 -
American Journal of Hematology Jul 2024
Chronic lymphocytic leukemia patients with chromosome 6q deletion as the sole cytogenetic abnormality display a high frequency of RPS15 mutations and have a poor prognosis.
PubMed: 38949404
DOI: 10.1002/ajh.27421