Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of ‘gene-negative’ individuals recruited to the 100 000 Genomes Project

Shovlin, CL; Almaghlouth, Fatma; Alsafi, Ali; Coote, Nicky; Rennie, Catherine; Wallace, G M F; Govani, Fatima S; Consortium, Genomics England Research

doi:10.1136/jmg-2023-109195

Cited by 7 publications

(4 citation statements)

References 19 publications

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“…In addition to HHT1, three other hereditary hemorrhagic telangiectasias (HHTs) have been identified, and they are all associated with mutations in components of the TGFβ signaling pathway (Table 1). 3,4 HHT affects 1 in 5000–8000 people worldwide, with a higher prevalence in some populations 5,6 . Mutations in ENG and ACVRL1 are the most common causes of HHT worldwide, and account for ~80% of the cases 1,7 .…”

Section: Introductionmentioning

confidence: 99%

Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild type allele

Gariballa,

Badawi,

Ali

2024

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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting 1 in 5000–8000 individuals. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is the most common HHT and manifests as diverse vascular malformations ranging from mild symptoms such as epistaxis and mucosal and cutaneous telangiectases to severe arteriovenous malformations (AVMs) in the lungs, brain or liver. HHT1 is caused by heterozygous mutations in the ENG gene, which encodes endoglin, the TGFβ homodimeric co‐receptor. It was previously shown that some endoglin HHT1‐causing variants failed to traffic to the plasma membrane due to their retention in the endoplasmic reticulum (ER) and consequent degradation by ER‐associated degradation (ERAD). Endoglin is a homodimer formed in the ER, and we therefore hypothesized that mixed heterodimers might form between ER‐retained variants and WT protein, thus hampering its maturation and trafficking to the plasma membrane causing dominant negative effects. Indeed, HA‐tagged ER‐retained mutants formed heterodimers with Myc‐tagged WT endoglin. Moreover, variants L32R, V105D, P165L, I271N and C363Y adversely affected the trafficking of WT endoglin by reducing its maturation and plasma membrane localization. These results strongly suggest dominant negative effects exerted by these ER‐retained variants aggravating endoglin loss of function in patients expressing them in the heterozygous state with the WT allele. Moreover, this study may help explain some of the variability observed among HHT1 patients due to the additional loss of function exerted by the dominant negative effects in addition to that due to haploinsufficiency. These findings might also have implications for some of the many conditions impacted by ERAD.

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Section: Introductionmentioning

confidence: 99%

Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild type allele

Gariballa,

Badawi,

Ali

2024

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“…In the case of GDF2 mutations generate an HHT-like syndrome classified as HHT5 [9]. Recent research suggests that mutations in EPHB4 or RASA1 may be responsible for the previously known as HHT3 and HHT4 types, as there is no evidence for the existence of two independent genes linked to chromosomes 5 and 7 [10]. EPHB4 and RASA1 variants cause capillary malformations-arteriovenous malformation (CM)/AVM syndrome.…”

Section: Introductionmentioning

confidence: 99%

Endothelial to Mesenchymal Transition in an HHT-like pediatric case of Multiple Pulmonary Arteriovenous Malformations

Lorente-Herraiz,

Cuesta,

Recio-Poveda

et al. 2024

Preprint

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Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connection between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5,000/8,000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-β pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao Criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8 years old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case of study follows a molecular pattern HHT-like. Therefore, molecular biology and cellular functional analysis has been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial to mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.

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“…In the case of GDF2 mutations, they generate an HHT-like syndrome classified as HHT5 [ 13 ]. Recent research suggests that mutations in EPHB4 or RASA1 may be responsible for those previously known as HHT3 and HHT4 types, as there is no evidence for the existence of two independent genes linked to chromosomes 5 and 7 [ 14 ]. EPHB4 and RASA1 variants cause capillary malformation–arteriovenous malformation (CM)/AVM syndrome.…”

Section: Introductionmentioning

confidence: 99%

Endothelial-to-Mesenchymal Transition in an Hereditary Hemorrhagic Telangiectasia-like Pediatric Case of Multiple Pulmonary Arteriovenous Malformations

Lorente-Herraiz,

Cuesta,

Recio-Poveda

et al. 2024

IJMS

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Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connections between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5000/8000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-β pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8-year-old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case under study follows a molecular pattern which is HHT-like. Therefore, molecular- biological and cellular-functional analyses have been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial-to-mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.

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Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of ‘gene-negative’ individuals recruited to the 100 000 Genomes Project

Cited by 7 publications

References 19 publications

Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild type allele

Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild type allele

Endothelial to Mesenchymal Transition in an HHT-like pediatric case of Multiple Pulmonary Arteriovenous Malformations

Endothelial-to-Mesenchymal Transition in an Hereditary Hemorrhagic Telangiectasia-like Pediatric Case of Multiple Pulmonary Arteriovenous Malformations

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