Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature Syndrome: A Systemic Review.

BACKGROUND: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome is a rare, hereditary, autoinflammatory disease. However, there are few cases reported in the literature. Therefore, we conduct this systematic review to summarize current evidence. METHODS: We conducted a systematic search in July 2021 using 11 different electronic databases. The included articles were screened according to our inclusion and exclusion criteria and assessed using an appropriate quality assessment tool. Then, the relevant data were extracted and summarized in tables accordingly. Each step of the previous one was done by 3 independent reviewers, and the conflicts were resolved by discussion and sometimes by counseling a senior member. RESULTS: The final included studies were 18 articles with 34 cases (mean age = 8 years, male/female = 19/15). The most reported symptoms and signs were fever 97.1%, erythematous plaques 76.5%, arthralgia 67.6%, hepatomegaly 61.8%, violaceous hue 61.8%, lipodystrophy in extremities 53.1% in addition to low weight and height. Rare features were reported too. The laboratories were not specific, which may be explained by a systemic inflammatory response. Vasculitis was the dominant feature in the skin biopsy, whereas the calcification in the basal ganglia was a prominent sign in many cases. CONCLUSIONS: Fever, skin lesions, and systemic inflammatory response were the prominent features of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. The clinical picture is the main guide in addition to the pathological findings. Mutation detection is the confirmatory test. Prednisolone is the most effective reported treatment for acute presentations in the literature.

Coexistence of Colon Perforation and Congenital Lipodystrophy.

Lipodystrophy (LD) is an acquired or congenital rare condition consisting of hyperlipidaemia, glucose intolerance/ insulin resistance, and almost complete absence and storage of adipose tissue. Colon perforations can be observed in type 4 congenital LD. Here, we aimed to present a case of sigmoid colon perforation which developed in a young woman with the diagnosis of LD. Extensive purulent peritonitis, significant wall thickening, and oedema in the sigmoid colon were detected during surgical exploration. Anterior resection with end colostomy procedure was then performed. Although bowel perforation has been theoretically reported to occur in LD, the presented case is the first adult patient in the literature. These individuals tend to develop colon perforation as a result of histological changes in their gastrointestinal tract. This situation should always be taken into consideration in order to avoid delay in diagnosis, especially in patients who present with abdominal pain and have a history of LD. Key Words: Intestinal perforation, Congenital lipodystrophy, Peritonitis, Sigmoid colon.

Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene.

POLD1 (DNA polymerase delta 1, catalytic subunit) is a protein-coding gene that encodes the large catalytic subunit (POLD1/p125) of the DNA polymerase delta (Polδ) complex. The consequence of missense or nonsynonymous SNPs (nsSNPs), which occur in the coding region of a specific gene, is the replacement of single amino acid. It may also change the structure, stability, and/or functions of the protein. Mutation in the POLD1 gene is associated with autosomal dominant predisposition to colonic adenomatous polyps, colon cancer, endometrial cancer (EDMC), breast cancer, and brain tumors. These de novo mutations in the POLD1 gene also result in autosomal dominant MDPL syndrome (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy). In this study, genetic variations of POLD1 which may affect the structure and/or function were analyzed using different types of bioinformatics tools. A total of 17038 nsSNPs for POLD1 were collected from the NCBI database, among which 1317 were missense variants. Out of all missense nsSNPs, 28 were found to be deleterious functionally and structurally. Among these deleterious nsSNPs, 23 showed a conservation scale of >5, 2 were predicted to be associated with binding site formation, and one acted as a posttranslational modification site. All of them were involved in coil, extracellular structures, or helix formation, and some cause the change in size, charge, and hydrophobicity.

Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics.

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with "mandibuloacral dysplasia type A" (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype-phenotype correlations.

A Shotgun Proteomic Platform for a Global Mapping of Lymphoblastoid Cells to Gain Insight into Nasu-Hakola Disease.

Nasu-Hakola Disease (NHD) is a recessively inherited systemic leukodystrophy disorder characterized by a combination of frontotemporal presenile dementia and lytic bone lesions. NHD is known to be genetically related to a structural defect of TREM2 and DAP12, two genes that encode for different subunits of the membrane receptor signaling complex expressed by microglia and osteoclast cells. Because of its rarity, molecular or proteomic studies on this disorder are absent or scarce, only case reports based on neuropsychological and genetic tests being reported. In light of this, the aim of this paper is to provide evidence on the potential of a label-free proteomic platform based on the Multidimensional Protein Identification Technology (MudPIT), combined with in-house software and on-line bioinformatics tools, to characterize the protein expression trends and the most involved pathways in NHD. The application of this approach on the Lymphoblastoid cells from a family composed of individuals affected by NHD, healthy carriers and control subjects allowed for the identification of about 3000 distinct proteins within the three analyzed groups, among which proteins anomalous to each category were identified. Of note, several differentially expressed proteins were associated with neurodegenerative processes. Moreover, the protein networks highlighted some molecular pathways that may be involved in the onset or progression of this rare frontotemporal disorder. Therefore, this fully automated MudPIT platform which allowed, for the first time, the generation of the whole protein profile of Lymphoblastoid cells from Nasu-Hakola subjects, could be a valid approach for the investigation of similar neurodegenerative diseases.

Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy.

CONTEXT: Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia. OBJECTIVE: Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy. METHODS: Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance. RESULTS: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ±â€…3.0, 6.5 ±â€…1.6, 6.5 ±â€…1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ±â€…1.7, 9.1 ±â€…1.3, 8.3 ±â€…1.7 mm, P < .01), and LV mass (140.7 ±â€…45.9, 128.7 ±â€…37.9, 110.9 ±â€…29.1 g, P < .01), and increased septal e' velocity (8.6 ±â€…1.7, 10.0 ±â€…2.1, 10.7 ±â€…2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD. CONCLUSION: Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype.

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in LMNA, and two additional variants, one each in SETX (g.intron10-13delCTT) and FUS (p.Gly167_Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the FUS variant appears to be protective against the effects of the SETX and the LMNA variants on cell viability and may indicate loss of interaction of FUS with SETX and/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.

Mandibuloacral dysplasia type A in five tunisian patients.

Mandibuloacral dysplasia with type A lipodystrophy is a rare autosomal recessive disorder characterized by craniofacial dysmorphism, type A lipodystrophy, clavicular dysplasia, and acroostelolysis. It is caused by homozygous or compound heterozygous missense mutations in LMNA gene. We report five Tunisian patients harboring the same homozygous c.1580G > A; p. (Arg527His) mutation in LMNA gene. The patients presented with typical features of mandibuloacral dysplasia including, prominent eyes, thin or beaked nose, dental overcrowding, mandibular hypoplasia, short and broad finger's distal phalanges with round tips and lipodystrophy type A. Newly recognized signs are growth hormone deficiency and dilated cardiomyopathy. Genotype-phenotype correlation found that at least one of the disease's LMNA mutant alleles involve one of the highly conserved aminoacids, residing in a key site domain for protein function within the C-terminal globular domain of A-type lamins. Also, the severity of the disease depends on the position in the protein's domain and on the type of substitution of the concerned aminoacid.

Neuropathological Alzheimer's Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes.

Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer's disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer's disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

Molecular and Cellular Bases of Lipodystrophy Syndromes.

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Exercise Increases Bone in SEIPIN Deficient Lipodystrophy, Despite Low Marrow Adiposity.

Exercise, typically beneficial for skeletal health, has not yet been studied in lipodystrophy, a condition characterized by paucity of white adipose tissue, with eventual diabetes, and steatosis. We applied a mouse model of global deficiency of Bscl2 (SEIPIN), required for lipid droplet formation. Male twelve-week-old B6 knockouts (KO) and wild type (WT) littermates were assigned six-weeks of voluntary, running exercise (E) versus non-exercise (N=5-8). KO weighed 14% less than WT (p=0.01) and exhibited an absence of epididymal adipose tissue; KO liver Plin1 via qPCR was 9-fold that of WT (p=0.04), consistent with steatosis. Bone marrow adipose tissue (BMAT), unlike white adipose, was measurable, although 40.5% lower in KO vs WT (p=0.0003) via 9.4T MRI/advanced image analysis. SEIPIN ablation's most notable effect marrow adiposity was in the proximal femoral diaphysis (-56% KO vs WT, p=0.005), with relative preservation in KO-distal-femur. Bone via µCT was preserved in SEIPIN KO, though some quality parameters were attenuated. Running distance, speed, and time were comparable in KO and WT. Exercise reduced weight (-24% WT-E vs WT p<0.001) but not in KO. Notably, exercise increased trabecular BV/TV in both (+31%, KO-E vs KO, p=0.004; +14%, WT-E vs WT, p=0.006). The presence and distribution of BMAT in SEIPIN KO, though lower than WT, is unexpected and points to a uniqueness of this depot. That trabecular bone increases were achievable in both KO and WT, despite a difference in BMAT quantity/distribution, points to potential metabolic flexibility during exercise-induced skeletal anabolism.

Lipodystrophies-Disorders of the Fatty Tissue.

Lipodystrophies are a heterogeneous group of physiological changes characterized by a selective loss of fatty tissue. Here, no fat cells are present, either through lack of differentiation, loss of function or premature apoptosis. As a consequence, lipids can only be stored ectopically in non-adipocytes with the major health consequences as fatty liver and insulin resistance. This is a crucial difference to being slim where the fat cells are present and store lipids if needed. A simple clinical classification of lipodystrophies is based on congenital vs. acquired and generalized vs. partial disturbance of fat distribution. Complications in patients with lipodystrophy depend on the clinical manifestations. For example, in diabetes mellitus microangiopathic complications such as nephropathy, retinopathy and neuropathy may develop. In addition, due to ectopic lipid accumulation in the liver, fatty liver hepatitis may also develop, possibly with cirrhosis. The consequences of extreme hypertriglyceridemia are typically acute pancreatitis or eruptive xanthomas. The combination of severe hyperglycemia with dyslipidemia and signs of insulin resistance can lead to premature atherosclerosis with its associated complications of coronary heart disease, peripheral vascular disease and cerebrovascular changes. Overall, lipodystrophy is rare with an estimated incidence for congenital (<1/1.000.000) and acquired (1-9/100.000) forms. Due to the rarity of the syndrome and the phenotypic range of metabolic complications, only studies with limited patient numbers can be considered. Experimental animal models are therefore useful to understand the molecular mechanisms in lipodystrophy and to identify possible therapeutic approaches.

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology.

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients' primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.

The common pathophysiologic threads between Asian Indian diabetic's 'Thin Fat Phenotype' and partial lipodystrophy: the peripheral adipose tissue transcriptomic evidences.

T2D is a complex disease with poorly understood mechanisms. In Asian Indians, it is associated with "thin fat" phenotype which resembles with partial lipodystrophy. We hypothesized that disturbed expression of lipodystrophy genes might play a role in T2D pathogenesis. Therefore, we attempted to establish a link between these two diseases by studying the overlap between the network of lipodystrophy genes and the differentially expressed genes (DEGs) in the peripheral subcutaneous adipose tissue of Asian Indians diabetics. We found that 16, out of 138 lipodystrophy genes were differentially regulated in diabetics and around 18% overlap between their network and the DEGs; the expression level of lipodystrophy genes showed an association with disease-related intermediate phenotypic traits among diabetics but not in the control group. We also attempted to individualize the diabetic patients based on ±2 fold altered expression of lipodystrophy genes as compared to their average expression in the control group. In conclusion, significant overlap exists between some of the lipodystrophy genes and their network with DEGs in the peripheral adipose tissue in diabetics. They possibly play a role in the pathogenesis of diabetes and individualization of diabetics is possible based on their altered expression in their peripheral adipose tissue.

Hepathic, biochemical, hematological, and histological effects of the ultracavitation in rabbits livers.

PURPOSE: To collect data capable of pointing out the effects of the ultracavitation treatment on the liver of rabbits after adipose tissue application, by means of histological analyses of the liver and hematological and biochemical exams. METHODS: This is an experimental study with 12 albino rabbits as sample, which were divided into 3 groups and submitted to a hypercaloric diet for one month. Subsequently, subjects underwent UCV treatment: 3 minutes, 30 W, continuous mode at 100%, every 2 ERAS = 441.02 J/cm2, intensity of 10w/cm2. They were then euthanized and underwent biopsy after 24 hours. RESULTS: After 48 hours from the ultracavitation treatment, the animals' livers presented greater amount of fat infiltration if compared to the amount presented 96 hours after the treatment. However, laboratory tests showed no alterations. Values were maintained within normal parameters of cholesterol, triglycerides, liver enzymes, hemoglobin and hematocrit levels. CONCLUSIONS: This study has identified that infiltrates may appear on livers after the treatment, despite high hematological and biochemical tests results. The fat infiltrates reduction 96 h after treatment suggests lower risks to animal health, if the period between applications is respected.

Dermolipectomia trocantérica em paciente pós-cirurgia bariátrica: relato de caso / Trochanteric dermolipectomy in a patient after bariatric surgery: case report

Introdução: Atualmente com o aumento das gastroplastias redutoras (cirurgia bariátrica) e grande perda ponderal, há também um aumento na procura destes pacientes pela cirurgia plástica. Uma das características destes pacientes é o excesso de tecido dermogorduroso que causa deformidades, principalmente nos membros inferiores, acometendo a região trocantérica. Objetivo: Relatar um caso de dermolipectomia trocantérica em paciente pós-cirurgia bariátrica, onde a lipoaspiração por si só não resolveria a correção da deformidade. Relato de caso: IPMS, sexo feminino, 55 anos, histórico de gastroplastia redutora (cirurgia bariátrica) com grande perda ponderal. Relata desconforto importante com a lipodistrofia e extensa flacidez em região trocantérica bilateral. Após avaliação pela equipe, foi optado por realizar dermolipectomia trocantérica bilateral, em janeiro de 2019, no Serviço de Cirurgia Plástica Osvaldo Saldanha. Discussão: Nos casos de lipodistrofia trocantérica com deformidades graves, a cicatriz da dermolipectomia em relação à deformidade é favorável quanto a escolha desta técnica, pois a lipoaspiração poderá agravar ainda mais a deformidade, sendo mandatório utilizar a técnica de dermolipectomia trocantérica para corrigila. Quanto à lipodistrofia com deformidade moderada há dúvida entre a relação do benefício e a deformidade resultante, sendo aplicada a técnica de acordo com a necessidade do paciente e, por fim, nos casos de lipodistrofia com deformidade leve, opta-se pela lipoaspiração devido à correção ser realizada sem grandes cicatrizes aparentes. Conclusão: Portanto, a lipoaspiração tem benefício nos casos de adiposidade localizada, limitando as indicações da técnica de dermolipectomia, em especial na região trocantérica, sem invalidá-la para casos selecionados, como o descrito neste relato de caso.

Introduction: Currently, with the increase in reducing gastroplasty (bariatric surgery) and the great weight loss, there is also an increase in the demand of these patients for plastic surgery. One of the characteristics of these patients is the excess of dermal adipose tissue that causes deformities, especially in the lower limbs, affecting the trochanteric region. Objective: To report a case of trochanteric dermolipectomy in a patient after bariatric surgery, where liposuction alone would not solve the correction of the deformity. Case report: IPMS, female, 55 years old, history of reducing gastroplasty (bariatric surgery) with great weight loss. She reports significant discomfort with lipodystrophy and extensive flacidity in the bilateral trochanteric region. After the team's evaluation, it was decided to perform bilateral trochanteric dermolipectomy, in January 2019, at the Plastic Surgery Service Osvaldo Saldanha Discussion: In cases of trochanteric lipodystrophy with severe deformities, the scar of dermolipectomy in relation to the deformity is favorable in terms of the choice of this technique, since liposuction may further aggravate the deformity, and it is mandatory to use the trochanteric dermolipectomy technique to correct it. Conclusion: Therefore, liposuction is beneficial in cases of localized adiposity, limiting the indications for the dermolipectomy technique, especially in the trochanteric region, without invalidating it for selected cases, as described in this case report.

Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome.

LMNA gene encodes for lamin A/C, attractive proteins linked to nuclear structure and functions. When mutated, it causes different rare diseases called laminopathies. In particular, an Arginine change in Histidine in position 527 (p.Arg527His) falling in the C-terminal domain of lamin A precursor form (prelamin A) causes mandibuloacral dysplasia Type A (MADA), a segmental progeroid syndrome characterized by skin, bone and metabolic anomalies. The well-characterized cellular models made difficult to assess the tissue-specific functions of 527His prelamin A. Here, we describe the generation and characterization of a MADA transgenic mouse overexpressing 527His LMNA gene, encoding mutated prelamin A. Bodyweight is slightly affected, while no difference in lifespan was observed in transgenic animals. Mild metabolic anomalies and thinning and loss of hairs from the back were the other observed phenotypic MADA manifestations. Histological analysis of tissues relevant for MADA syndrome revealed slight increase in adipose tissue inflammatory cells and a reduction of hypodermis due to a loss of subcutaneous adipose tissue. At cellular levels, transgenic cutaneous fibroblasts displayed nuclear envelope aberrations, presence of prelamin A, proliferation, and senescence rate defects. Gene transcriptional pattern was found differentially modulated between transgenic and wildtype animals, too. In conclusion, the presence of 527His Prelamin A accumulation is further linked to the appearance of mild progeroid features and metabolic disorder without lifespan reduction.