ORCID Profile
0000-0001-5826-0276
Current Organisations
Hospital Infantil Universitario Niño Jesús
,
Universidad de Alcalá de Henares
,
Universidad Autónoma de Madrid
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Publisher: Springer Science and Business Media LLC
Date: 04-11-2022
DOI: 10.1038/S41467-022-34349-8
Abstract: Embryonic development is dictated by tight regulation of DNA replication, cell ision and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5 , in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-08-2010
Abstract: The neuronal circuits involved in the regulation of feeding behavior and energy expenditure are soft-wired, reflecting the relative activity of the postsynaptic neuronal system, including the anorexigenic proopiomelanocortin (POMC)-expressing cells of the arcuate nucleus. We analyzed the synaptic input organization of the melanocortin system in lean rats that were vulnerable (DIO) or resistant (DR) to diet-induced obesity. We found a distinct difference in the quantitative and qualitative synaptology of POMC cells between DIO and DR animals, with a significantly greater number of inhibitory inputs in the POMC neurons in DIO rats compared with DR rats. When exposed to a high-fat diet (HFD), the POMC cells of DIO animals lost synapses, whereas those of DR rats recruited connections. In both DIO rats and mice, the HFD-triggered loss of synapses on POMC neurons was associated with increased glial ensheathment of the POMC perikarya. The altered synaptic organization of HFD-fed animals promoted increased POMC tone and a decrease in the stimulatory connections onto the neighboring neuropeptide Y (NPY) cells. Exposure to HFD was associated with reactive gliosis, and this affected the structure of the blood-brain barrier such that the POMC and NPY cell bodies and dendrites became less accessible to blood vessels. Taken together, these data suggest that consumption of an HFD has a major impact on the cytoarchitecture of the arcuate nucleus in vulnerable subjects, with changes that might be irreversible due to reactive gliosis.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2015
DOI: 10.1038/NCOMMS6949
Abstract: Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, ‘browning’ of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27 -null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare ex le where adipose inflammation and hepatic insulin resistance are disassociated.
Publisher: The Endocrine Society
Date: 09-2010
DOI: 10.1210/JC.2010-0489
Abstract: To date, 16 IGFALS mutations in 21 patients with acid-labile subunit (ALS) deficiency have been reported. The impact of heterozygosity for IGFALS mutations on growth is unknown. The study evaluates the impact of heterozygous expression of IGFALS mutations on phenotype based on data collected by the International ALS Consortium. Patient information was derived from the IGFALS Registry, which includes patients with IGFALS mutations and family members who were either heterozygous carriers or homozygous wild-type. Within each family, the effect of IGFALS mutations on stature was analyzed as follows: 1) effect of two mutant alleles (2ALS) vs. wild-type (WT) 2) effect of two mutant alleles vs. one mutant allele (1ALS) and 3) effect of one mutant allele vs. wild-type. The differences in height sd score (HtSDS) were then pooled and evaluated. Mean HtSDS in 2ALS was -2.31 +/- 0.87 (less than -2 SDS in 62%) in 1ALS, -0.83 +/- 1.34 (less than -2 SDS in 26%) and in WT, -1.02 +/- 1.04 (less than -2 SDS in 12.5%). When analyses were performed within in idual families and pooled, the difference in mean HtSDS between 2ALS and WT was -1.93 +/- 0.79 between 1ALS and WT, -0.90 +/- 1.53 and between 2ALS and 1ALS, -1.48 +/- 0.83. Heterozygosity for IGFALS mutations results in approximately 1.0 SD height loss in comparison with wild type, whereas homozygosity or compound heterozygosity gives a further loss of 1.0 to 1.5 SD, suggestive of a gene-dose effect. Further studies involving a larger cohort are needed to evaluate the impact of heterozygous IGFALS mutations not only on auxology, but also on other aspects of the GH/IGF system.
No related grants have been discovered for Jesús Argente.