Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Sarmento, Aquiles Sales Craveiro; Medeiros, Lázaro Batista de Azevedo; Agnez-Lima, Lucymara Fassarella; Lima, Josivan Gomes de; Campos, Julliane Tamara Araújo de Melo

doi:10.1155/2018/5207608

Cited by 17 publications

(8 citation statements)

References 130 publications

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“…We propose that the direct interaction we have identified with seipin may facilitate the recruitment of perilipin 1 to these maturing lipid droplets. Seipin has been reported to interact with a variety of proteins that mediate lipid droplet biogenesis [37] and directly to phospholipids on the droplet surface [38], [39]. Supporting our findings are an evolutionarily conserved functional interaction of the yeast orthologue of seipin with a novel yeast perilipin-like protein Pet10p [40], and a reported interaction between seipin and the lipid droplet protein ADRP/Plin2 [41].…”

Section: Resultssupporting

confidence: 80%

Discovering metabolic disease gene interactions by correlated effects on cellular morphology

Jiao

Ahmed

Sim

et al. 2019

Molecular Metabolism

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Objective Impaired expansion of peripheral fat contributes to the pathogenesis of insulin resistance and Type 2 Diabetes (T2D). We aimed to identify novel disease–gene interactions during adipocyte differentiation. Methods Genes in disease-associated loci for T2D, adiposity and insulin resistance were ranked according to expression in human adipocytes. The top 125 genes were ablated in human pre-adipocytes via CRISPR/CAS9 and the resulting cellular phenotypes quantified during adipocyte differentiation with high-content microscopy and automated image analysis. Morphometric measurements were extracted from all images and used to construct morphologic profiles for each gene. Results Over 10 7 morphometric measurements were obtained. Clustering of the morphologic profiles accross all genes revealed a group of 14 genes characterized by decreased lipid accumulation, and enriched for known lipodystrophy genes. For two lipodystrophy genes, BSCL2 and AGPAT2, sub-clusters with PLIN1 and CEBPA identifed by morphological similarity were validated by independent experiments as novel protein–protein and gene regulatory interactions. Conclusions A morphometric approach in adipocytes can resolve multiple cellular mechanisms for metabolic disease loci; this approach enables mechanistic interrogation of the hundreds of metabolic disease loci whose function still remains unknown.

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Section: Resultssupporting

confidence: 80%

Discovering metabolic disease gene interactions by correlated effects on cellular morphology

Jiao

Ahmed

Sim

et al. 2019

Molecular Metabolism

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“…It is less clear why infections are linked to BSCL2 deficiency, but a direct effect in macrophages is credible. Seipin plays an important, evolutionarily conserved role in the biogenesis of lipid droplets [ 23 ], organelles that have been shown to regulate macrophage function and infection resolution, as has lipid metabolism [ 16 , 24 ]. In addition, BSCL2 /seipin deficiency has been shown to induce ER stress [ 23 ], a process that has also been implicated in altered innate immunity and myeloid cell dysfunction in type 2 diabetes and atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Bscl2 Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy

Roumane

Mcilroy

Balci

et al. 2021

JCM

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Congenital Generalized Lipodystrophy type 2 (CGL2) is the most severe form of lipodystrophy and is caused by mutations in the BSCL2 gene. Affected patients exhibit a near complete lack of adipose tissue and suffer severe metabolic disease. A recent study identified infection as a major cause of death in CGL2 patients, leading us to examine whether Bscl2 loss could directly affect the innate immune response. We generated a novel mouse model selectively lacking Bscl2 in the myeloid lineage (LysM-B2KO) and also examined the function of bone-marrow-derived macrophages (BMDM) isolated from global Bscl2 knockout (SKO) mice. LysM-B2KO mice failed to develop lipodystrophy and metabolic disease, providing a model to study the direct role of Bscl2 in myeloid lineage cells. Lipopolysaccharide-mediated stimulation of inflammatory cytokines was not impaired in LysM-B2KO mice or in BMDM isolated from either LysM-B2KO or SKO mice. Additionally, intracellular fate and clearance of bacteria in SKO BMDM challenged with Staphylococcus aureus was indistinguishable from that in BMDM isolated from littermate controls. Overall, our findings reveal that selective Bscl2 deficiency in macrophages does not critically impact the innate immune response to infection. Instead, an increased susceptibility to infection in CGL2 patients is likely to result from severe metabolic disease.

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“…Among the variants we found in this gene, three were already reported as VUS, while the other two variants, p.Ser230Asn and p.Ser353Thr, were present in ExAC database at a very low frequency (MAF < 0.00001). Among them, the former was located in the highly conserved functional domain, analogously to the p.Ala282Thr identified by us, while the Ser353 was a cAMP and cGMP-dependent protein kinase phosphorylation site, which allowed us to speculate about the potential pathogenicity of the latter variant [63].…”

Section: Discussionmentioning

confidence: 77%

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Scarlino¹,

Domi²,

Pozzi³

et al. 2020

IJMS

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Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.

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Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Cited by 17 publications

References 130 publications

Discovering metabolic disease gene interactions by correlated effects on cellular morphology

Discovering metabolic disease gene interactions by correlated effects on cellular morphology

Bscl2 Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

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