A Rare Recurring Gain-of-Function Variant in BMPR2 Causes Neurodevelopmental Phenotypes in Humans and Flies

Authors

• Jung-Wan Mok
• Carrie L Welch
• Haley A Dostalik
• Zhi Tan
• Ariel Brautbar
• Maria DesCartes
• Erica T Gray
• Alejandro Iglesias
• Scott D McLean
• Morgan Nutter
• Olivia Daugherty
• Amber Begtrup
• Ingrid M Wentzensen
• Yufeng Shen
• Damian W Young
• Martin M Matzuk
• Oguz Kanca
• Michael F Wangler
• Hugo J Bellen
• Wendy K Chung
• Shinya Yamamoto

Language

English

Publication Date

10-1-2026

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2026.08.019

PMID

42767215

PMCID

PMC13662929

PubMedCentral® Posted Date

10-15-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Bone morphogenetic protein receptor type 2 (BMPR2) encodes an evolutionarily conserved serine/threonine kinase that phosphorylates type-1 BMP receptors to mediate intercellular communication upon ligand binding. Loss-of-function variants in BMPR2 are known to cause pulmonary arterial hypertension and other cardiovascular disorders. Here, we report a rare recurrent missense variant in BMPR2 (c.1126G>A [GenBank: NM_001204] [p.Glu376Lys]) identified in six individuals, who all present with neurodevelopmental phenotypes including autism spectrum disorder and global developmental delay. Trio analysis demonstrates de novo occurrence of this variant in at least five of the individuals. Using the fruit fly Drosophila melanogaster, we show that this variant behaves as a gain-of-function allele that acts in a ligand-independent but type-1 BMP receptor-dependent manner. BMPR2-specific inhibitors suppress excessive BMP activation induced by p.Glu376Lys variant expression in Drosophila, demonstrating its hypermorphic property. Finally, we show that this variant causes neurodevelopmental defects in flies when expressed in neurons or glial cells. Given that BMPR2 is expressed in various neural cell types in the human brain, ectopic activation of BMP signaling in multiple cell types is likely to contribute to the neurodevelopmental phenotypes observed in the probands.

Keywords

Animals, Humans, Bone Morphogenetic Protein Receptors, Type II, Drosophila melanogaster, Phenotype, Gain of Function Mutation, Female, Male, Mutation, Missense, Signal Transduction, Neurodevelopmental Disorders, Child, Neurodevelopment, Child, Preschool

Published Open-Access

yes

Recommended Citation

Mok, Jung-Wan; Welch, Carrie L; Dostalik, Haley A; et al., "A Rare Recurring Gain-of-Function Variant in BMPR2 Causes Neurodevelopmental Phenotypes in Humans and Flies" (2026). Faculty, Staff and Students Publications. 8162.
https://digitalcommons.library.tmc.edu/baylor_docs/8162