Isolated Left Ventricular Apical Hypoplasia without Lamin A/C Gene Mutation

Abstract Isolated left ventricular apical hypoplasia is a rare cardiomyopathy, with a broad range of clinical presentations. Since this entity was already described in association with osteomuscular diseases, mutation in the Lamin A/C gene has been regarded as a possible cause of this disease. This study describes the case of an asymptomatic teenager with isolated left ventricular apical hypoplasia and arthrogriposis but with no mutations in the entire Lamin A/C gene.

Analysis of a child with congenital muscular dystrophy due to a novel variant of the LMNA gene / 中华医学遗传学杂志

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.

Generation of a Hutchinson-Gilford progeria syndrome monkey model by base editing

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.

Inflammatory myopathy in the context of an unusual overlapping laminopathy

Summary Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

Clinical and genetic features of limb-girdle muscular dystrophy type 1B: a case report / 中国当代儿科杂志

This article reports a case of limb-girdle muscular dystrophy type 1B (LGMD1B) caused by a novel splicing heterozygous mutation in the LMNA gene. The proband presented with progressive aggravation of weakness in walking. There was no atrophy of the scapular muscles and the lower-extremity proximal muscles, with normal muscle tension of the extremities, grade 4 muscle strength in the upper and lower extremities, and positive Gower sign. The level of creatine kinase was 779 U/L. Muscle hematoxylin-eosin staining showed muscular dystrophy, and there was no significant reduction in the expression of Lamin A protein. Second-generation sequencing revealed a novel splicing heterozygous mutation, c.810+2T>C, in the LMNA gene, while this locus was normal in his parents. GERP++RS software predicted that the mutation site was highly conservative. Human Splice Finder and Spliceman software predicted that the mutation might be a pathogenic mutation. ExPASy software predicted that the new amino acid sequence became shorter. There were two sequences of mRNA in the patient's muscle: one was the normal sequence, which accounted for 92.2%; the other was partial intron 4 retention, which was the abnormal splice variant accounting for 7.8%. LGMD1B is a type of autosomal dominant inherited myopathy caused by a mutation in the LMNA gene located on the autosomal 1q22. This study extends the mutation spectrum of the LMNA gene and provides help to the diagnosis of LGMD1B.

Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

A novel c.563 T>G, p.L189R lamin A/C mutation in identical twins with dilated cardiomyopathy

No abstract available.

Myeloid and erythroid hematopoietic transcription factor expression decline after knockdown ofgenes in zebrafish embryos / 浙江大学学报·医学版

To investigate the effect ofgene down-regulation on early hematopoietic development of zebrafish.Phosphorodiamidate morpholino oligomer (PMO) technology was used to downregulategene expression in Zebrafish. Zebrafish embryos injected phosphorodiamidate morpholino antisense oligonucleotide ofgene mRNA by microinjection at unicellular stage were taken as the experimental group, and those injected meaningless phosphorodiamidate morpholino antisense oligonucleotide were taken as the control. The embryos were collected at 18, 24, 30 and 36 hpf after the fertilization. The real-time fluorescent quantitative PCR (RT-PCR) and whole embryohybridization methods were used to detect the expression of myeloid hematopoietic transcription factorand erythroid hematopoietic transcription factorin zebrafish.RT-PCR showed that the expressions ofanddecreased in the experimental group compared with the control group (all<0.05). Whole embryohybridization showed that the blue-black positive hybridization signals ofandin experimental group were shallow than those in the control group.Myeloid hematopoietic and erythroid hematopoietic of zebrafish are blocked with the downregulation ofgene.

Expression and significance of VEGF, miR-205 and target protein Ezrin and Lamin A/C in ovarian cancer / 中南大学学报(医学版)

OBJECTIVE@#To analyze the expression of vascular endothelial growth factor (VEGF), miR-205, Ezrinand Lamin A/C in ovarian cancer tissues.@*METHODS@#The expression of VEGF in the serum of epithelial ovarian cancer and that of healthy volunteers were detected by enzyme-linked immunosorbent assay; the expressions of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, Ezrin and Lamin A/C were detected by immunohistochemistry and the micro-vessel density (MVD) of CD31 was detected by immunohistochemistry in epithelial ovarian cancer, benign ovarian and normal ovarian specimens; and the expression of miR-205, Ezrin and Lamin A/C were detected by real-time PCR in epithelial ovarian cancer, benign ovarian and normal ovarian specimens.@*RESULTS@#The expression of VEGF in the serum of epithelial ovarian cancer patients (116.10± 11.94) was significantly higher than that of healthy volunteers (40.04±4.97, P0.05). The average length of MVD in the epithelial ovarian cancer specimens (7.56±0.51), was significantly higher than that in the normal ovarian specimens (1.22±0.56, P0.05). The relative expression level of miR-205 was 0.106±0.035 in the epithelial ovarian cancer specimens, which was significantly higher than that in the normal ovarian specimens (0.0007±0.0005, P0.05). The positive expression rates of Ezrin and Lamin A/C in the epithelial ovarian cancer specimens were 51.7% and 60.3%, respectively, which were significantly lower than those in the benign ovarian and the normal ovarian specimens (P0.05). The relative expression levels of Ezrin and Lamin A/C mRNA in the epithelial ovarian cancer specimens were (0.026±0.003) and (0.060±0.007), respectively, which were significantly lower than those in the normal ovarian specimens (P0.05) .@*CONCLUSION@#VEGF is significantly expressed in the serum of epithelial ovarian cancer patients; and miR-205 is up-regulated in the epithelial ovarian cancer specimens. Ezrin and Lamin A/C are down-regulated in the epithelial ovarian cancer samples. VEGF, miR-205 and target protein may be associated with the invasion and metastasis of epithelial ovarian cancer.

Analysis of a case with typical Hutchinson-Gilford progeria syndrome with scleroderma-like skin changes and review of literature / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore clinical, radiographical and genetic characteristics of classical Hutchinson-Gilford progeria syndrome (HGPS).</p><p><b>METHOD</b>Data of a case of HGPS diagnosed at Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology was analyzed and related literature was reviewed.</p><p><b>RESULT</b>At the age of 8 months, the affected-infant presented with characteristic manifestation such as short stature, low weight, frontal bossing, alopecia, prominent scalp veins, micrognathia with a vertical midline groove in the chin, sclerodermatous skin, knee joints contracture with a horse-riding stance, and limited range of movement of ankle joints. Blood test showed blood platelet count (416-490) ×10(9)/L. Lower extremities MRI showed reduced subcutaneous fat. LMNA gene analysis showed that the affected-infant carried typical heterozygous mutation: c. 1824C>T (p. G608G), while his parents were normal. At the age of 13 months, X-rays showed short distal phalanges and clavicles with acro-osteolysis. After following up for 15 months, his appearance of progeria became more apparent. As far as we know, there are only 2 cases of classical HGPS confirmed by gene analysis in China.</p><p><b>CONCLUSION</b>Classical HGPS should be considered when infants appeared with sclerodermatous skin. Genetic analysis could help to diagnose classical HGPS as early as possible and avoid unnecessary investigations. In addition, affected-infants need to be long term followed-up and provided genetic counseling.</p>

Association between LMNA mutation and familial and idiopathic dilated cardiomyopathy patients in Xinjiang / 中华心血管病杂志

<p><b>OBJECTIVE</b>To explore the association between LMNA gene mutation and familiar dilated cardiomyopathy (DCM) (FDCM) and idiopathic DCM (IDCM) in Uygurs and Hans people in Xinjiang area.</p><p><b>METHODS</b>Peripheral blood samples were collected from 28 family member with FDCM and 123 sporadic patients with IDCM(56 Uygur patients and 67 Han patients), 80 Uygur and 80 Han people were chosen as normal controls. PCR was used to amplify the 12 exons of LMNA gene. The amplified products were sequenced and compared with the standard sequence in the NCBI to determine the mutation sites.</p><p><b>RESULTS</b>Transmission of the allele C and T of rs4641 was similar in Han FDCM patients. One new variation(c.1714C>T) located at exon 10 of LMNA gene was identified in 1 Han patient with IDCM, this mutation caused an amino acid substitution (R572C). In Uygurs people, rs553016 polymorphism was significant different between IDCM and control groups (P < 0.05). Logistic regression revealed that rs553016 was an independent risk factor for Uygurs patients with IDCM (OR = 3.178, P = 0.035).</p><p><b>CONCLUSIONS</b>LMNA rs4641 is not associated with FDCM of Hans people in Xinjiang while LMNA mutation is associated with IDCM and rs533106 polymorphism is an independent risk factor for Uygurs patients with IDCM.</p>

Avaliação bioquímica, hormonal e genética das famílias de duas pacientes brasileiras portadoras de lipodistrofia parcial familiar tipo 2 / Biochemical, hormonal and genetic evaluation of the families of two Brazilian patients with type 2 familial partial lipodystrophy

OBJETIVO: Avaliar características clínicas, bioquímicas, hormonais e genéticas de familiares de duas pacientes portadoras de lipodistrofia parcial familiar (FPLD) tipo 2. MATERIAIS E MÉTODOS: Foram avaliados 50 indivíduos de duas famílias brasileiras não relacionadas a partir de dois propósitos com fenótipo de FPLD. Foi confirmada a mutação no éxon 8 do gene LMNA em 18 destes e identificada a substituição em heterozigose no códon 482, resultando na mutação p.R482W. Com base na presença ou não da mutação, os indivíduos foram separados em afetados e não afetados, e comparados quanto a parâmetros clínicos, bioquímicos e hormonais. RESULTADOS: Indivíduos afetados tiveram 2,8 vezes mais chance de manifestar diabetes e síndrome dos ovários policísticos (SOP), maiores índices HOMA-IR, níveis de insulina e de triglicérides e menores níveis de leptina. Essas alterações precedem o início do diabetes, pois foram evidenciadas nos afetados diabéticos e não diabéticos. Foi constatada heterogeneidade fenotípica entre os portadores da mutação. CONCLUSÃO: A mutação no gene da LMNA é determinante de alterações clínicas, bioquímicas e hormonais que implicam deterioração metabólica nos portadores da mutação.

OBJECTIVE: To evaluate clinical, biochemical, hormonal and genetic characteristics of relatives of two patients with familial partial lipodystrophy (FPLD) type 2. MATERIALS AND METHODS: Fifty subjects, members of two non-related Brazilian families from two different probands with FPLD phenotype, were evaluated. A mutation in exon 8 of LMNA gene was confirmed in 18 of them, and a heterozygous substitution at codon 482 was identified, predicting a p.R482W mutation. Based on the presence or absence of the mutation, subjects were classified in affected and unaffected, and compared in terms of clinical, biochemical and hormonal parameters. RESULTS: Affected subjects were 2.8 times more likely to manifest diabetes and PCOS, higher HOMA-IR, insulin and triglyceride levels, and lower levels of leptin. These changes preceded the onset of diabetes, because they were observed in diabetic and non-diabetic affected patients. A phenotypic heterogeneity was found among mutation carriers. CONCLUSION: A mutation in the LMNA gene is a determinant of clinical, biochemical and hormonal changes that imply in metabolic deterioration in mutation carriers.

Hutchinson-Gilford Progeria Syndrome with G608G LMNA Mutation

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.

Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer / 癌症

Through advances in technology, the genetic basis of cancer has been investigated at the genomic level, and many fundamental questions have begun to be addressed. Among several key unresolved questions in cancer biology, the molecular basis for the link between nuclear deformation and malignancy has not been determined. Another hallmark of human cancer is aneuploidy; however, the causes and consequences of aneuploidy are unanswered and are hotly contested topics. We found that nuclear lamina proteins lamin A/C are absent in a significant fraction (38%) of human breast cancer tissues. Even in lamin A/C-positive breast cancer, lamin A/C expression is heterogeneous or aberrant (such as non-nuclear distribution) in the population of tumor cells, as determined by immunohistology and immunofluorescence microscopy. In most breast cancer cell lines, a significant fraction of the lamin A/C-negative population was observed. To determine the consequences of the loss of lamin A/C, we suppressed their expression by shRNA in non-cancerous primary breast epithelial cells. Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation, resembling that of cancer cells, as observed by immunofluorescence microscopy. The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization. We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.

Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Mutations in the lamin A/C gene (LMNA) may cause familial dilated cardiomyopathy (dilated cardiomyopathy) characterized by early onset atrio-ventricular block (A-V block) before the manifestation of dilated cardiomyopathy and high risk of sudden death due to ventricular arrhythmia, which is very similar to the phenotype of gap junction related heart disease. This study aimed to determine the expression and localization of connexins in neonatal myocytes transfected with wild-type (WT) or mutant LMNA to elucidate how these mutations cause heart diseases.</p><p><b>METHODS</b>We studied the connexin 43 (Cx43) and connexin 40 (Cx40) expression in cultured neonatal myocytes transfected with wild-type (WT) or mutant LMNA (Glu82Lys (E82K) and Arg644Cys (R644C)) using confocal imaging and Western blotting analysis.</p><p><b>RESULTS</b>Cx43 protein expression was reduced by 40% in cells transfected with LMNA E82K than that in cells transfected with WT LMNA cDNA. Confocal imaging showed that the Cx43 located inside the cells by LMNA E82K. By contrast, LMNA E82K mutation had no effect on expression and localization of Cx40. LMNA R644C transfection did not show any significant effects on gap junctions at all.</p><p><b>CONCLUSIONS</b>Our findings suggest that LMNA E82K significantly reduced the Cx43 expression and altered its localization which may be one of the pathological mechanisms underlying LMNA-related heart disease.</p>

Lamin C protein deficiency in the primary fibroblasts from a new laminopathy case with ovarian cystadenoma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Laminopathies are a group of rare genetic disorders characterized by multiple-tissue degeneration. We describe a new laminopathy with ovarian cystadenoma and explore its molecular etiology.</p><p><b>METHODS</b>The case is a 15-year-old girl who presents the prominent progeroid disorders, multiple system degeneration and early-onset cystadenoma of the ovary. Candidate genes including LMNA, ZMPSTE24, PPAR G, INSR and WRN were sequenced to screen for DNA variants. The mRNA and protein expression levels of LMNA were examined in primary fibroblasts. The pathophysiological events such as morphologic alterations, cell senescence, cell proliferation, apoptosis and pRb as well as p53 protein expressions were also investigated in primary fibroblasts.</p><p><b>RESULTS</b>No mutation was identified in the candidate genes screened. Nuclear abnormalities including nuclear blebs, mislocalization of lamin A/C were evident in the patient fibroblasts. Ultrastructurally, nucleus exhibited nuclear herniation and almost complete loss of peripheral heterochromatin. In addition, lamin C protein expression was markedly reduced whereas lamin A protein level was normal and no prelamin A was detected in the primary fibroblasts. Although the senescence-associated beta-galactosidase staining of patient' cells was negative, cells in S phase increased in accompany with a decrease in pRb protein expression. Furthermore, increases in apoptotic cell death and p53 expression were observed.</p><p><b>CONCLUSIONS</b>Our data suggest that selective deficiency of lamin C protein is associated with a case of laminopathy with ovarian cystadenoma. The abnormalities in nuclear structure and alterations in gene expression such as the decrease in pRb and increase in p53 may be responsible for the multiple tissue degeneration.</p>

Novel LMNA Gene Mutation in a Patient With Atypical Werner's Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner's syndrome are representative types of progeroid syndrome. LMNA (Lamin A/C) gene mutation with atypical Werner's syndrome have recently been reported. Atypical Werner's syndrome with the severe metabolic complications, the extent of the lipodystrophy is associated with A133L mutation in the LMNA gene and these patients present with phenotypically heterogeneous disorders. We experienced a 15-yr-old Korean female with progeroid features, generalized lipodystrophy, hypertriglyceridemia, fatty liver, steatohepatitis, and type 2 diabetes mellitus. Skin fibroblasts from the patient showed marked abnormal nuclear morphology, compared with that from normal persons. Gene analysis revealed that this patient had T506del of exon 2 in the LMNA gene. We report here the first case of atypical Werner's syndrome with frameshift mutation that was caused by T506del.

R25G mutation in exon 1 of LMNA gene is associated with dilated cardiomyopathy and limb-girdle muscular dystrophy 1B / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Mutations 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.</p><p><b>METHODS</b>All 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.</p><p><b>RESULTS</b>Ten 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).</p><p><b>CONCLUSIONS</b>The 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.</p>

Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygous LMNA p. T10I mutation / Lipoatrofia generalizada atípica e resistência insulínica grave devido à mutação p. T10I em heterozigose no gene LMNA

Lipodystrophies are a group of heterogeneous disorders characterized by the loss of adipose tissue and metabolic complications. The main familial forms of lipodystrophy are Congenital Generalized Lipodystrophy and Familial Partial Lipodystrophy (FPLD). FPLD may result from mutations in the LMNA gene. Besides FPLD, mutations in LMNA have been shown to be responsible for other inherited diseases called laminopathies. Here we describe the case of a 15-year-old girl who was referred to our service due to diabetes mellitus and severe hypertriglyceridemia. Physical examination revealed generalized loss of subcutaneous fat, confirmed by DEXA (total body fat 8.6 percent). As the patient presented with pubertal-onset of generalized lipodystrophy and insulin resistance, molecular analysis of the LMNA gene was performed. We identified a heterozygous substitution in exon 1 (c.29C>T) predicting a p.T10I mutation. In summary, we describe an atypical phenotype of lipodistrophy associated with a de novo appearance of the p.T10I mutation in LMNA gene.

As lipodistrofias são um grupo heterogêneo de doenças caracterizadas por perda de tecido adiposo e complicações metabólicas. As formas hereditárias mais importantes de lipodistrofias são: lipodistrofia congênita generalizada e lipodistrofia parcial familiar (LDPF). LDPF resulta de mutações no gene LMNA que codificam as lâminas tipo A. Além da LDPF, mutações no gene LMNA são responsáveis por outras doenças hereditárias, denominadas laminopatias. Descrevemos o caso de uma paciente de 15 anos de idade encaminhada por diabetes melito e hipertrigliceridemia grave. Ao exame físico, apresentava perda generalizada de gordura subcutânea que foi confirmada por DEXA (gordura corporal total 8,6 por cento). Como a paciente apresentava perda de gordura de início na puberdade e resistência insulínica, foi realizada análise molecular do gene LMNA. Identificamos uma substituição em heterozigose no éxon 1 (c.29C>T), resultando na mutação p.T10I. Em sumário, um caso de fenótipo atípico de lipodistrofia generalizada devido à mutação de novo p.T10I no gene LMNA é descrito.

Induction of Apoptosis by Genistein in Human Melanoma Cells / 대한해부학회지

Genistein is a naturally occurring isoflavone that has been identified predominantly in soybean. It has been found that genistein can inhibit the growth of various cancer cell lines. Melanoma continues to increase in incidence in many parts of the world and remains among the top six cancers as a cause of death and morbidity. Understanding and overcoming resistance mechanism(s) of melanoma to apoptosis would therefore facilitate identification of new therapeutic targets and development of new treatments. This study was undertaken to investigate whether genistein induced apoptosis on human melanoma cells (G361). Genistein had a significant dose- and time-dependent inhibitory effect on the viability of G361 cells. The death of cells was further demonstrated to be due to apoptosis characterized by chromatin condensation and apoptotic bodies by hoechst staining, and DNA electrophoresis. p53 levels were not altered by genistein treatment. Genistein treatment induced caspase-3 cleavage and activation. Poly (ADP-ribose)-polymerase (PARP) and DNA fragmentation factor 45 (DFF45), which are caspase-3 substrates, were cleaved during genistein-induced apoptosis. It was found that the caspase-6 substrate lamin A was cleaved, whose cleavage has been reported to be necessary for complete condensation of DNA during apoptosis. The expression level and phosphorylation of focal adhesion kinase (FAK) were reduced by genistein treatment. These results suggest that genistein may constitute a potential antitumor compound against melanoma occurring at oral mucosa and skin.