Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment

A Small Supernumerary Marker Derived from the Pericentromeric Region of Chromosome 5: Case Report and Delineation of Partial Trisomy 5p Phenotype

A 17-year-old girl presented with a distinct phenotype mainly featuring craniofacial dysmorphism, including a disproportioned large, round, elongated face; hypertelorism; deep-set eyes with short palpebral fissures; obesity (BMI 37), and a neuropsychiatric disorder with high-functioning autism. Postnatal conventional cytogenetic analyses from peripheral blood revealed a mosaic small supernumerary marker chromosome (sSMC) with a mos 47,XX,+mar[7]/46,XX[43] karyotype. By cenM-FISH technique, the sSMC was identified as a ring derivative of chromosome 5. Metaphase FISH analysis with a set of dedicated probes defined its origin from the pericentromeric region of chromosome 5, including the NIPBL gene at 5p13.2. Such sSMCs, exceedingly rare in the literature, underlie proximal trisomy 5p. In order to delineate a core phenotype of proximal trisomy 5p, we compared our patient's features with those of 6 patients found in the literature with similar der(5) chromosomes. Furthermore, a dozen individuals with 5p13 (micro)duplication syndrome was compared and discussed. We identified highly distinctive craniofacial dysmorphism, obesity, and intellectual disability and/or autism spectrum disorder as typical features of proximal 5p trisomy. In the critical region (band 5p13), the NIPBL gene is likely to be a major determinant of the neurobehavioral phenotype, and its presence at the sSMC level may be relevant to predict clinical outcome

De novo 13q13.3-21.31 deletion involving RB1 gene in a patient with hemangioendothelioma of the liver

Interstitial deletions of the long arm of chromosome 13 (13q) are related with variable phenotypes, according to the size and the location of the deleted region. The main clinical features are moderate/severe mental and growth retardation, cranio-facial dysmorphism, variable congenital defects and increased susceptibility to tumors. Here we report a 3-year-old girl carrying a de novo 13q13.3-21.32 interstitial deletion. She showed developmental delay, growth retardation and mild dysmorphism including curly hair, high forehead, short nose, thin upper lip and long philtrum. An abnormal mass was surgically removed from her liver resulting in a hemangioendothelioma. Array analysis allowed us to define a deleted region of about 27.87 Mb, which includes the RB1 gene. This is the first report of a 13q deletion associated with infantile hemangioendothelioma of the liver

Chronic granulomatous disease with gastrointestinal presentation: diagnostic pitfalls and novel ultrastructural findings

Chronic granulomatous disease (CGD) is a rare congenital disorder, characterized by defects in the NADPH oxidase biochemical pathway leading to defective phagocytic cell function. Life-threatening infections caused by a large spectrum of bacteria and fungi represent the major clinical problem [1]. The diagnosis is usually easily achieved in the first years of life and appropriate anti-infectious prophylactic treatment significantly increases the overall survival. As the overall knowledge of the disease increases, also the recognition of patients with a delayed and more insidious onset increases. We report on the case of an Italian child with an exclusive gastrointestinal presentation, which led to a delayed diagnosis. We also document for the first time ultrastructural changes in the microvillous architecture in this syndrome

Integrating sediment core and satellite sensing approaches to assess recent phytoplankton bloom trajectories in a large reservoir

In this work we integrated two approaches that are rarely used together in addressing the responses of biota to multiple environmental stressors sediment cores and satellite images. The study area is a large subtropical reservoir (750 km2) that recurrently suffers severe cyanobacteria blooms, yet the trajectory of blooms since the building of the reservoir (in 1979) until the onset of the ongoing water quality monitoring program (ongoing since the year 2000) was unknown. In 2015 we performed sediment core studies, which were published in 2020, and our findings suggested that phytoplankton blooms initiated in 2003, about 24 years after the reservoir was built. Moreover, in this reservoir, as part of the current monitoring program, specific algorithms for chlorophyll estimation using satellites have been developed and published. Such algorithms allow phytoplankton chlorophyll estimation since 1984, thanks to the continuity of the Landsat mission (about 16 years prior to the monitoring program). Hence, we used images from 1984-2015 to explore if we could complement the information obtained using sediment cores. For this, we processed Landsat 5, 7 and 8 Landsat images (482, 350 and 67, respectively) in different areas of the reservoir, and calculated anomalies in chlorophyll (whenever chlorophyll was > 85 μg L-1). We found that before 2003, in average anomalies were only recorded about one time per year, whereas after 2003 the frequency of anomalies markedly increased (average 8 anomalies per year). Overall, the patterns found using sediment cores were like those encountered using satellite estimation of chlorophyll. Thus, these tools could be complementary used for analyzing recent trends (last 30 years, since satellites are operative in space) of phytoplankton trajectories.Fil: de Tezanos Pinto, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Drozd, Andrea Alejandra. Universidad Nacional de Avellaneda; ArgentinaFil: Postorivo, A.. Universidad Nacional de Avellaneda; ArgentinaFil: Gangi, D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Plastani, María Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; ArgentinaFil: Laprida, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; ArgentinaFil: Lami, Andrea. No especifíca;Fil: Dubois, Nathalie. Eidgenossische Technische Hochschule zurich (eth Zurich);Fil: Bordet, Facundo. No especifíca;Fil: Gogorza, Claudia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. Sede Olavarría del Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires | Universidad Nacional del Centro de la Pcia. de Bs.as. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. Sede Olavarría del Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires; ArgentinaFil: Frau, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto Nacional de Limnología. Universidad Nacional del Litoral. Instituto Nacional de Limnología; ArgentinaInternational Association of Limnogeologists - International Paleolimnology Association Joint Meeting: Lagos, Memorias del TerritorioBarilocheArgentinaInternational Paleolimnological AssociationInternational Association of Limnogeolog

Four Copies of SNCA Responsible for Autosomal Dominant Parkinson's Disease in Two Italian Siblings

Background. Parkinson's disease (PD) is mostly characterized by alpha-synuclein (SNCA) aggregation and loss of nigrostriatal dopamine-containing neurons. In this study a novel SNCA multiplication is described in two siblings affected by severe parkinsonism featuring early onset dyskinesia, psychiatric symptoms, and cognitive deterioration. Methods. SNCA dosage was performed using High-Density Comparative Genomic Hybridization Array (CGH-Array), Multiple Ligation Dependent Probe Amplification (MLPA), and Quantitative PCR (qPCR). Genetic analysis was associated with clinical evaluation. Results. Genetic analysis of siblings showed for the first time a 351 Kb triplication containing SNCA gene along with 6 exons of MMRN1 gene in 4q22.1 and a duplication of 1,29Mb of a genomic region flanking the triplication. Conclusions. The identification of this family indicates a novel mechanism of SNCA gene multiplication, which confirms the genomic instability in this region and provides data on the genotype-phenotype correlation in PD patients

Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterised by pyramidal, cerebellar, and autonomic disturbances. Duplication of the LMNB1 gene is the genetic cause of ADLD, yet the pathogenetic mechanism is not defined. In this study, we analysed cells and muscle tissue from three patients affected by ADLD, carrying an extra copy of the LMNB1 gene. Lamin B1 levels were dramatically increased in ADLD nuclei, both in skin fibroblasts and skeletal muscle fibres. Since lamin B1 is known to bind Oct-1, a transcription factor involved in the oxidative stress pathway, we investigated Oct-1 fate in ADLD. Oct-1 recruitment to the nuclear periphery was increased in ADLD cells, while nucleoplasmic localisation of the transcription factor under oxidative stress conditions was reduced. Importantly, lamin B1 degradation occurring in some, but not all ADLD cell lines, slowed down lamin B1 and Oct-1 accumulation. In skeletal muscle, focal disorganisation of sarcomeres was observed, while IIB-myosin heavy chain, an Oct-1 target gene, was under-expressed and rod-containing fibres were formed. These data show that a high degree of regulation of lamin B1 expression is implicated in the different clinical phenotypes observed in ADLD and show that altered Oct-1 nuclear localisation contributes to the disease phenotype