No abstract available.
Cardiomyopathy, Dilated* ; Humans ; Lamin Type A ; Twins, Monozygotic*

Cardiomyopathy, Dilated ; genetics ; Lamin Type A ; genetics

Humans ; Cardiomyopathies/genetics* ; Laminopathies ; Lamin Type A/genetics* ; Mutation

The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to detachment of lamina-associated domains (LADs) from the nuclear periphery accompanied with global chromatin redistribution and decompaction. Consequently, the inter-chromosomal as well as inter-compartment interactions are increased, but the structure of topologically associating domains (TADs) is not affected. Using live-cell genomic loci tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, chromatin compaction, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting their crucial roles in chromatin higher-order structure and chromatin dynamics.
Chromatin ; Chromosomes ; Genome ; Humans ; Lamin Type B/genetics*

Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp veins and sclerodermatous skin. This abnormal appearance began at age of 1 yr. On serological and hormonal evaluation, all values are within normal range. He was neurologically intact with motor and mental development. An echocardiogram showed calcification of aortic and mitral valves. Hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography. He is on low dose aspirin to prevent thromboembolic episodes and on regular follow up. Gene study showed typical G608G (GGC- > GGT) point mutation at exon 11 in LMNA gene. This is a rare case of Hutchinson-Gilford progeria syndrome confirmed by genetic analysis in Korea.
Child, Preschool ; Humans ; Lamin Type A/*genetics ; Male ; Point Mutation ; Progeria/diagnosis/*genetics ; Prognosis ; Republic of Korea

BACKGROUNDMutations of the LMNA gene encoding lamin A and C are associated with dilated cardiomyopathy (DCM), conduction system defects and skeletal muscle dystrophy. Here we report a family with a mutation of the LMNA gene to identify the relationship between genotype and phenotype.

METHODSAll 30 members of the family underwent clinical and genetic evaluation. A mutation analysis of the LMNA gene was performed. All of the 12 exons of LMNA gene were extended with polymerase chain reaction (PCR) and the PCR products were screened for gene mutation by direct sequencing.

RESULTSTen members of the family had limb-girdle muscular dystrophy (LGMD) and 6 are still alive. Two patients suffered from DCM. Cardiac arrhythmias included atrioventricular block and atrial fibrillation; sudden death occurred in 2 patients. The pattern of inheritance was autosomal dominant. Mutation c.73C > G (R25G) in exon 1 encoding the globular domains was confirmed in all of the affected members, resulting in the conversion of arginine (Arg) to glycine (Gly).

CONCLUSIONSThe mutation R25G in exon 1 of LMNA gene we reported here in a Chinese family had a phenotype of malignant arrhythmia and mild LGMD, suggesting that patients with familial DCM, conduction system defects and skeletal muscle dystrophy should be screened by genetic testing for the LMNA gene.

Adult ; Cardiomyopathy, Dilated ; genetics ; Exons ; Humans ; Lamin Type A ; genetics ; Muscular Dystrophies, Limb-Girdle ; genetics ; Mutation

OBJECTIVETo investigate the effect of a novel LMNA gene mutation E82K found in a Chinese family with dilated cardiomyopathy on cell cycle of HEK293 cells.

METHODS(1) Human wild type full-length LMNA gene cDNA was subcloned into eukaryotic expression vector pTracer-CMV and point mutation was introduced into the cDNA. LMNA gene wild type and mutant E82K LMNA gene were transfected into HEK293 cells respectively and stable cell lines resistant to antibiotic were obtained 4 weeks later. (2) Cell cycle changes were analyzed by flow cytometry in HEK293 cells transfected with wild type and mutant E82K LMNA gene and empty vector in the presence of 0.8 mmol/L H(2)O(2).

RESULTSCell circle was arrested at G0/G1 phase in the cells transfected with mutated E82K LMNA gene and at G2/M phase in other cell groups in the presence of H(2)O(2).

CONCLUSIONCell circle was arrested at G0/G1 phase in the cells transfected with E82K LMNA gene in the presence of H(2)O(2) in HEK293 cells.

Cardiomyopathy, Dilated ; genetics ; Cell Cycle ; Cell Line ; Flow Cytometry ; Humans ; Lamin Type A ; genetics ; Mutation ; Transfection

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.
Animals ; Disease Models, Animal ; Female ; Gene Editing ; Humans ; Lamin Type A/metabolism* ; Macaca fascicularis ; Progeria/pathology*

OBJECTIVE: To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of LMNA gene and explore its pathogenicity. METHODS: The 1-year-and-1-month-old boy has presented with motor development delay and elevation of muscle enzymes for more than half a year. Congenital myopathy was suspected. Following muscle biopsy, HE staining, immunostaining and electron microscopy were conducted to clarify the clinical diagnosis. Meanwhile, DNA was extracted from the child and his parents' peripheral venous blood samples. Trio-whole exome sequencing (trio-WES) was carried out to detect pathogenic variant in the child. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Both light and electron microscopy showed a large area of necrotic muscle tissues with infiltration of inflammatory cells. Immunohistochemistry revealed a large amount of muscle cells to be diffusely positive for Dysferlin. The patient's motor delays, elevations of muscle enzymes and histopathological results suggested a clinical diagnosis of CMD. A de novo missense c.1072G>A (p.E358K) variant was detected in the LMNA gene by trio-WES. The variant was unreported previously (PS2) and was absent from major allele frequency databases (PM2). It was a loss of function variant and was considered as hotspot variant in the LMNA gene (PM1) as the amino acid (E), located in position 358, was highly conserved, and change of this amino acid was found to cause destruction of the filament domain (AA: 30-386), which may result in serious damage to the intermediate filament protein. Furthermore, c.1072G>A (p. E358K) in LMNA gene was also predicted to be pathogenic based on MutationTaster, PROVEAN and PolyPhen-2 (PP3) analysis. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PS2+PM1+PM2+PP3). CONCLUSION The child's condition may be attributed to the de novo missense c.1072 G>A (p.E358K) variant of the LMNA gene. Above discovery has expanded the variant spectrum of the LMNA gene.
Gene Frequency ; Genomics ; Humans ; Infant ; Lamin Type A/genetics* ; Male ; Muscular Dystrophies/genetics* ; Mutation ; Whole Exome Sequencing

Lamin B1 is one of the essential members of the nuclear lamina protein family. Its main function is to maintain the integrity of nuclear skeleton, as well as to participate in the cell proliferation and aging by affecting the chromosome distribution. gene expression, and DNA damage repair. The abnormal expression of lamin B1 is related to certain diseases, including neurological diseases [e.g. neural tube defects (NDTs), adult-onset autosomal dominant leukodystrophy (ADLD)] and tumors (e.g. pancreatic cancer). It is also a potential tumor marker as well as drug target. Further research on lamin B1 will help people understand the molecular mechanism of the emergence and development of neural system diseases and tumors, and define a new future in drug target.
Cell Nucleus ; Gene Expression ; Humans ; Lamin Type B ; physiology ; Neoplasms ; Nervous System Diseases