One Overactive Gene Could Explain Autism Found in Six Children

A GENE known to cause lung disease when it’s weakened may cause developmental delay and autism when it’s overactive. Weakened versions of BMPR2 are a known cause of pulmonary arterial hypertension, a disorder of the blood vessels in the lungs. Now an apparently overactive version has turned up in six children with developmental delay or autism. In fruit flies, that version acts like a switch stuck in the “on” position. Most cell receptors stay quiet until a signaling molecule docks with them, but this one fires on its own. A team led from Baylor College of Medicine and Texas Children’s Duncan Neurological Research Institute in Houston reports the work in the American Journal of Human Genetics.

BMPR2 encodes a receptor in the bone morphogenetic protein (BMP) pathway, a signaling system that helps shape bone, blood vessels and the developing brain. More than 500 BMPR2 variants have been classed as pathogenic in people with pulmonary arterial hypertension, yet none had been tied to a neurological condition.

Six Children, One Identical Change

The trail began in exome sequencing records (the protein-coding stretch of a genome) from children with neurodevelopmental diagnoses, held by a clinical testing company and by a large autism research cohort, where one spelling change in BMPR2 kept reappearing: glutamate swapped for lysine at position 376, and absent from a reference database of population genomes. In five of the children, sequencing both parents showed the change was new. In the sixth, the one parent sequenced didn’t carry it. Five of the six had global developmental delay and four had been diagnosed with autism; some also had seizures, anxiety or hyperactivity, and the picture varied a lot from child to child.

A clue, then, not a proof. The paper’s own grading, under American College of Medical Genetics criteria, rates the change only likely pathogenic and BMPR2 a candidate gene, since no link to any neurodevelopmental disorder existed yet; the accompanying news release goes further, calling it a new cause.

Switched On Without a Trigger

Why flies? Because they carry a receptor of their own, called Wishful thinking, that matches the human protein at 49% of positions in its working end (the kinase domain), so the team built flies that make the human version in chosen tissues and compared the variant against the normal one. The normal human protein thickened fly wing veins, the variant did it far more severely. Expressed mildly throughout the body, the variant was lethal before adulthood, whereas flies carrying either of two variants known to cause pulmonary arterial hypertension survived with no visible wing defects, as you’d expect of variants that have lost function.

“Finding the identical genetic change in multiple unrelated children was an important clue, but it did not tell us how the change was affecting brain development,” says Shinya Yamamoto, corresponding author of the paper and a principal investigator at the Duncan institute and associate professor at Baylor. Flies could supply the missing step: in the eye, the variant raised signaling across the whole patch of tissue where it was made, whether or not the pathway’s usual trigger, a signaling molecule, was around.

Silencing the trigger molecule in the wing left the variant’s effects untouched, yet cutting the dose of a partner receptor, Thickveins, which relays the signal onward, suppressed them: the variant seems to need the relay but not the trigger. A computer prediction of the protein’s shape hints at why, with the swapped amino acid nudging the kinase toward its active form. Two experimental compounds designed to block BMPR2 then damped the excess signaling, though only in dissected fly tissue bathed in them. Mixed into fly food, they left the wing defects alone, which the authors put down to the compounds possibly never reaching the tissue. Hence the dish.

Glia Took the Worst of It

Expressed in every fly neuron, the variant switched signaling on in only a subset of them, and those flies lived; neurons mostly shrugged it off, though in motor neurons it added extra synaptic connections, the swollen boutons where a nerve meets muscle. In glia, the brain’s support cells, the effect was far harsher, lethal when the variant was expressed in all of them and lethal again when confined to one subtype, the perineurial glia lining the larval brain’s surface.

“These compounds are research tools, not treatments ready for clinical use,” Yamamoto cautions. The design carries limits of its own: six children is a small group, the human protein was overexpressed in flies whose neural cells and circuitry differ from ours, and mammalian cells have yet to be tested.

The authors reckon the same fly assays might sort other uncertain BMPR2 variants, particularly those in the kinase domain, into overactive and underactive. There is a further echo in fragile X syndrome. Fly and mouse models of that condition have implicated extra BMPR2 activity in its synaptic defects. The authors also note overlaps between fragile X features and those of their six children.

The obvious next test is a mammalian one: which brain cells, in mice or in people, are most vulnerable to too much of this signal? Until then: six families with a candidate explanation, and a receptor that refuses to wait its turn.

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