rs200330818 — GDF2

GDF2 Arg68Leu — When BMP9 Cannot Mature

Your blood vessels are not static pipes. They are living structures continuously reshaped by molecular signals — and one of the most important of those signals in the vascular system is BMP9¹¹ BMP9
BMP9 (bone morphogenetic protein 9) is a secreted ligand of the TGF-beta superfamily. Despite the name, it is primarily active in vascular biology, not bone — it is the physiological ligand for the endothelial receptor ALK1 and its co-receptor endoglin. The GDF2 gene encodes BMP9, and the p.Arg68Leu variant — a single amino acid substitution in the prodomain of the protein — disrupts BMP9's ability to mature into its active form, impairs signaling through the ALK1 pathway, and has been linked to a rare vascular malformation syndrome now classified as hereditary hemorrhagic telangiectasia type 5 (HHT5).

HHT is an autosomal dominant disorder affecting an estimated 1 in 5,000 people globally. It is characterized by abnormal blood vessel formations — telangiectases (tiny dilated vessels visible on skin and mucous membranes) and arteriovenous malformations (AVMs) in internal organs including the lungs, liver, and brain. Recurrent nosebleeds (epistaxis) are almost universally the first symptom. GDF2 variants account for a small fraction of HHT cases, and the clinical phenotype of HHT5 overlaps with but differs from the more common HHT1 (ENG) and HHT2 (ACVRL1) forms in ways that have clinical management implications.

The Mechanism

BMP9 is secreted as a large precursor — a prodomain²² prodomain
The prodomain is a regulatory segment that must be cleaved off to release the active mature ligand. For BMP9, the prodomain and the mature domain remain non-covalently associated after cleavage, forming what is called a 'procomplex' attached to a mature signaling domain. Cleavage by furin-family proteases releases the active mature BMP9 dimer, which then binds to ALK1 and its co-receptors (endoglin, BMPR2) on endothelial cell surfaces.

The Arg68 residue sits within the prodomain. In vitro expression studies of the p.Arg68Leu mutant showed that the precursor protein is expressed normally but fails to produce mature BMP9 dimer efficiently³³ fails to produce mature BMP9 dimer efficiently
Processing to mature BMP9 was far less efficient for p.Arg68Leu than wild-type protein; in ALK1 signaling assays the variant showed approximately 79% of wild-type activity at 10 pg/ml and 79% at 30 pg/ml equivalent dilutions — a modest but consistent and reproducible reduction. The biological consequence is reduced BMP9/ALK1/SMAD1/5/8 signaling in endothelial cells, which normally suppresses pathological angiogenesis and maintains AV differentiation. Loss of this brake promotes disorganized vascular sprouting, telangiectasia formation, and AV fistula development.

The Evidence

The p.Arg68Leu variant was identified by Wooderchak-Donahue et al. (2013)⁴⁴ Wooderchak-Donahue et al. (2013)
Wooderchak-Donahue WL et al. Am J Hum Genet 2013 93:530-7 — sequenced 191 patients with suspected HHT who were negative for ENG, ACVRL1, and SMAD4; identified three pathogenic GDF2 missense variants including Arg68Leu in a proband who met clinical HHT criteria (epistaxis and cutaneous telangiectases). The variant co-segregated with disease in family members: the proband's father and sister both carried p.Arg68Leu and reported epistaxis. Functional assays in C2C12 and ATDC5 cells transfected with ALK1 confirmed reduced BMP9 signaling. This variant was absent from 5,400 control exomes, 1000 Genomes, and dbSNP at time of publication, consistent with a rare pathogenic allele under negative selection.

The variant has since been documented in subsequent case literature. A 2025 pediatric HHT cohort study at CHOP identified the p.Arg68Leu variant in one patient (patient 6 in that series), who presented with epistaxis and mucocutaneous telangiectases; the patient's father, carrying the same variant, also had epistaxis — confirming the family segregation pattern originally described.

ClinVar (VCV000088651) classifies the G>T transversion (p.Arg68Leu) as "Likely Pathogenic" for HHT5, based on functional evidence of altered GDF2 protein processing and the clinical presentation of the carrier and affected family members. A second variant at the same codon — p.Arg68His (G>A, ClinVar VCV000646500) — is classified as "Uncertain Significance," highlighting that not every amino acid change at position 68 has the same functional impact.

Separate work has reinforced the dose-sensitivity of BMP9 signaling. Chomette et al. (2023)⁵⁵ Chomette et al. (2023)
Chomette L et al. Am J Med Genet A 2023 191:2157-2167 — described a child with homozygous GDF2 missense at the cleavage site who had both PAH and HHT features; heterozygous parents were entirely asymptomatic, illustrating how homozygous loss of BMP9 is far more severe than haploinsufficiency showed that BMP9 processing mutations can cause pediatric PAH. Heterozygous parents of the affected child remained asymptomatic, consistent with variable expressivity in GDF2-HHT5 generally.

Practical Actions

HHT5 is actionable: vascular screening detects AVMs before they become symptomatic emergencies. Pulmonary AVMs can cause paradoxical emboli (stroke) and hemoptysis. Brain AVMs risk hemorrhagic stroke. Hepatic AVMs cause high-output heart failure in advanced disease. Screening protocols adapted from HHT1/HHT2 guidelines are applied to GDF2 carriers.

The phenotype of GDF2-HHT5 may be milder and less penetrant than HHT1/HHT2 — some carriers have only epistaxis with no solid organ AVMs. Nonetheless, clinical evaluation and baseline screening are warranted in all confirmed or suspected carriers, as visceral AVMs are present in a meaningful proportion of published cases and can be clinically silent until they cause an acute event.

Genetic counseling is essential: HHT5 is autosomal dominant, meaning each first-degree relative of a carrier has a 50% chance of inheriting the variant. The variable expressivity means a parent with only mild epistaxis can have a child with pulmonary AVMs.

Interactions

GDF2 (BMP9) signals through the same endothelial receptor complex as ENG (HHT1) and ACVRL1/ALK1 (HHT2). Variants in ENG and ACVRL1 that reduce receptor availability or signaling would be expected to compound with GDF2 loss-of-function, though digenic HHT from GDF2 plus ENG/ACVRL1 has not been formally documented in published case series. Similarly, SMAD4 loss-of-function (HHT-juvenile polyposis overlap syndrome) disrupts the downstream effector of the same pathway.

BMPR2 is the type II receptor for BMP9, and pathogenic BMPR2 variants are the most common cause of hereditary pulmonary arterial hypertension (hPAH). GDF2 variants can cause both HHT5 and PAH through reduced BMP9/ALK1 signaling, suggesting that concurrent BMPR2 variants might amplify PAH risk in GDF2 carriers, though this interaction has not been systematically studied.