A homozygous variant in growth and differentiation factor 2 (<scp>GDF2</scp>) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

Aukema, Sietse M.; Brinke, Gerdien A. ten; Timens, Wim; Vos, Yvonne J.; Accord, Ryan E.; Kraft, Karianne E.; Santing, Michiel; Streefland, E.; Diemen, Cleo C. van; Vrijlandt, Elianne J.L.E.; Hulzebos, Christian V.; Kerstjens-Frederikse, Wilhelmina S.

doi:10.1002/ajmg.a.61743

Cited by 9 publications

(13 citation statements)

References 73 publications

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“…Noteworthy, in 2020, a homozygous variant in BMP9 was associated with lymphatic dysplasia with hydrothorax and immune hydrops fetalis 135 …”

Section: Bmp9 and Bmp10 Functions In The Cardiovascular System: Specific And Redundant Rolesmentioning

confidence: 99%

“…Noteworthy, in 2020, a homozygous variant in BMP9 was associated with lymphatic dysplasia with hydrothorax and immune hydrops fetalis. 135 Although therapeutic strategies targeting BMP9/10-ALK1 pathway have been proposed, as discussed below, it is not clear whether this pathway should be activated or inhibited, especially in PAH. Nevertheless, these mutations highlight the importance of this pathway in vascular homeostasis.…”

Section: In Vivo: What Do We Learn From Human Diseases?mentioning

confidence: 99%

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BMP9 and BMP10: Two close vascular quiescence partners that stand out

Desroches-Castan

Tillet

Bouvard

et al. 2021

Developmental Dynamics

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Bone morphogenetic proteins (BMPs) are dimeric transforming growth factor ß (TGFß) family cytokines that were first described in bone and cartilage formation but have since been shown to be involved in many pleiotropic functions. In human, there are 15 BMP ligands, which initiate their cellular signaling by forming a complex with two copies of type I receptors and two copies of type II receptors, both of which are transmembrane receptors with an intracellular serine/threonine kinase domain. Within this receptor family, ALK1 (activin receptor-like kinase 1), which is a type I receptor mainly expressed on endothelial cells, and BMPRII (BMP Receptor type II), a type II receptor also highly expressed on endothelial cells, have been directly linked to two rare vascular diseases: hereditary hemorrhagic telangiectasia (HHT), and pulmonary arterial hypertension (PAH), respectively. BMP9 (gene name GDF2) and BMP10, two close members of the BMP family, are the only known ligands for the ALK1 receptor. This specificity gives them a unique role in physiological and pathological angiogenesis and tissue homeostasis. The aim of this current review is to present an overview of what is known about BMP9 and BMP10 on vascular regulation with a particular emphasis on recent results and the many questions that remain unanswered regarding the roles and specificities between BMP9 and BMP10.

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“…Noteworthy, in 2020, a homozygous variant in BMP9 was associated with lymphatic dysplasia with hydrothorax and immune hydrops fetalis 135 …”

Section: Bmp9 and Bmp10 Functions In The Cardiovascular System: Specific And Redundant Rolesmentioning

confidence: 99%

Section: In Vivo: What Do We Learn From Human Diseases?mentioning

confidence: 99%

BMP9 and BMP10: Two close vascular quiescence partners that stand out

Desroches-Castan

Tillet

Bouvard

et al. 2021

Developmental Dynamics

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“…Wang et al, 2016;Wang et al, 2019) as well as an "HHT-like" syndrome characterized by cutaneous telangiectases and AVMs (Liu et al, 2020;Wooderchak-Donahue et al, 2013). Intriguingly, a recent report of a family with a child with non-immune hydrops fetalis, hydrothorax, and lymphatic dysplasia has identified a homozygous GDF2 (p.[Arg151Ter];[Arg151Ter}) mutation (Table 1; Aukema et al, 2020). Again, protein levels were not determined, so it is not known if this mutation is subject to, or escapes from nonsense-mediated decay (Lappalainen et al, 2013).…”

Section: Assessment Of Alternate Codon Utilization In the P[gln26ter] Bmp9 Mutantmentioning

confidence: 99%

Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an “HHT‐like” syndrome in children

Hodgson

Ruiz

McDonald

et al. 2021

Molec Gen & Gen Med

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Background: Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra-rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases. Methods: Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE-luciferase reporter 2 of 13 |

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“…19 New pathways involving lymphangiogenesis and remodelling have also been identified and involve genes such as PIEZO1, 20 EPHB4, 21 CALCR 22 and GDF2. 23 In 2020, heterozygous missense mutations in angiopoietin-2 (ANGPT2) were reported to cause primary lymphoedema with reduced penetrance and variable expressivity in five unrelated families, 24 implicating another endothelial growth factor receptor pathway, the ANGPT2-TIE2 tyrosine kinase pathway. In these families, lymphoedema was not severe and tended to resolve during childhood.…”

Section: Developmental Defectsmentioning

confidence: 99%

BiallelicANGPT2loss-of-function causes severe early-onset non-immune hydrops fetalis

et al. 2021

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BackgroundHydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis.Methods and resultsWhole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 (ANGPT2) variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted.ConclusionPathogenic heterozygous ANGPT2 missense variants were recently shown to cause autosomal dominant primary lymphoedema. ANGPT2 is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessive ANGPT2-related disorder in humans.

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A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

Abstract: Frederikse, W. S. (2020). A homozygous variant in growth and differentiation factor 2(GDF2)may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis.

Cited by 9 publications

References 73 publications

BMP9 and BMP10: Two close vascular quiescence partners that stand out

BMP9 and BMP10: Two close vascular quiescence partners that stand out

Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an “HHT‐like” syndrome in children

BiallelicANGPT2loss-of-function causes severe early-onset non-immune hydrops fetalis

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