Dataset Information

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism.

ABSTRACT: BACKGROUND:Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far. METHODS:We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment. RESULTS:The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding. CONCLUSION:Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.

SUBMITTER: Radio FC

PROVIDER: S-EPMC6014450 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism.

Radio Francesca Clementina FC Di Meglio Lavinia L Agolini Emanuele E Bellacchio Emanuele E Rinelli Martina M Toscano Paolo P Boldrini Renata R Novelli Antonio A Di Meglio Aniello A Dallapiccola Bruno B

Molecular genetics & genomic medicine 20180303 3

<h4>Background</h4>Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far.<h4>Methods</h4>We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLV ...[more]

PMID: 29500860

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Project description:The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies. There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3. Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication. It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as the expression of cytokines that produce the cytokine storm. The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response. Highlights • SARS-CoV-2 causes serious disease via two distinct mechanisms• One mechanism is damage to the alveolar wall (microangiopathy) associated with high viral copy numbers• The other mechanism is circulating viral capsid proteins that dock on ACE2+ endothelia• The ACE2+ endothelia are most prominent in the subcutaneous fat and brain• Endocytosis of viral capsid protein by endothelia induces cell death, cytokine expression, and complement activation (endothelialitis)

Dataset Information

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism.

Publications

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism.

Similar Datasets

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