From lab bench to bedside – research in mice leads to answers for undiagnosed human neurodevelopmental conditions

(Press-News.org) Nearly 30 years ago, researchers began studying the gene Astn1, which encodes the cell adhesion protein astrotactin 1 in mice, and its role in brain development. During this time, they learned a great deal about the function of astroactin 1 in neuronal migration and the developmental problems that emerge when the protein fails.

This story has now come full circle – the findings in mice are helping to provide answers to undiagnosed human conditions. Researchers at Baylor College of Medicine, Texas Children Hospital and collaborating institutions have established a gene-disease association between human astrotactin 1 gene, ASTN1, and neurodevelopmental disorders. They showed that loss-of-function versions of ASTN1, which encode a defective protein that cannot fulfill its function, cause a broad spectrum of neurodevelopmental conditions in children. The findings, published in the American Journal of Human Genetics, have provided answers to families that until now had no diagnosis for the condition.

What does astroactin1 do?

“Astrotactin 1 is a protein that helps young brain cells move to the right location while the brain is forming,” said co-author Dr. Daniel Calame, instructor of pediatric neurology and developmental neurosciences at Baylor. “This migration is essential for building the cerebral cortex (thinking part of the brain), the cerebellum (movement and coordination) and the hippocampus (memory). If the gene ASTN1 is defective and astrotactin1 doesn’t work properly, neurons may not reach the right places, disrupting brain organization and function. Animal studies show that mice lacking Astn1 gene have trouble with balance, coordination and proper neuron placement.”

ASTN1 works closely with another gene, ASTN2, which helps control the placement of the ASTN1 protein on the cell surface. Because of this partnership, faults in both genes can amplify neurological problems.

Before this study, ASTN1 was suspected but not confirmed to cause human neurodevelopmental disorders. ASTN1 variants have been reported in nine individuals with neurodevelopmental disorders; however, clinical information was minimal, so a gene-disease connection could not be established. In addition, there are no entries linking ASTN1 and neurodevelopmental disorders in the main clinical genomic databases.

Connecting genes and disease

Looking to determine whether ASTN1 genes were associated with neurodevelopmental disorders, Calame, co-author Dr. Jesse Levine, neuroimmunology fellow in pediatric neurology and developmental neuroscience at Baylor, and their colleagues, analyzed genomic data and clinical information in 18 children from 12 unrelated families. All the children had rare defective gene variants in both copies of their ASTN1 gene, and one had one defective copy of ASTN1 and one of ASTN2.

All 18 children studied had developmental delays or intellectual disability, but the specific symptoms varied widely. “We found that ASTN1-related neurodevelopmental conditions range from mild to profound developmental delay or intellectual disability and can be associated with autism, attention-deficit hyperactivity disorder and epilepsy. We also found cases with altered facial features, low muscle tone and balance problems,” Levine explained.

Brain imaging showed that some children had normal scans, but most showed alterations in brain structures. These included a thinner or malformed corpus callosum (the band connecting the right and the left sides of the brain), abnormalities in the cerebellum, which can affect coordination, and reduced brain volume in some cases.

“This study provides a thorough description of characteristics associated with ASTN1-related neurodevelopmental conditions and thereby strengthens the connection with this gene and probably with other genes like ASTN2,” Calame said. “We propose that the neurodevelopmental conditions in these children emerge from disrupted neuronal migration in the developing brain, particularly in the cerebellum and cerebral cortex, where ASTN1 mediates neuronal migration.”

Importantly, the findings provide answers to the families seeking explanations for their child’s condition. “These children had not received a diagnosis for years,” Calame said. “Our study has provided a long-awaited answer to the nature of their condition, ending their diagnostic odyssey.”

The work was conducted by the BCM-GREGoR (Genomics Research to Elucidate the Genetics of Rare diseases) Research Center as part of the NHGRI’S GREGoR Consortium.

For a complete list of the contributors to this work, see the publication.

The authors would like to acknowledge the families who participated in the study. This study was supported in part by a grant from the U.S. National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHBLI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG, UM1 HG006542); an NHGRI grant as part of the GREGoR Consortium (U01 HG011758); an NHGRI grant to the Baylor College of Medicine Human Genome Sequencing Center (U54HG003273); and the US National Institute of Neurological Disorders and Stroke (NINDS) (R35NS105078). Further support was provided by NINDS 1K23 NS125126-01A1 and the Rett Syndrome Research Trust fellowship award from the International Rett Syndrome Foundation (IRSF grant #3701-1), the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number K12NS098482, an MDA Development Grant (873841), the GREGoR Consortium Research Grant, Research to Prevent Blindness – MEE Grant 2023, P30EY014104, and the Foundation Fighting Blindness (EGI-GE-1218-0753-UCSD). Additional support was provided by the Research, Development and Innovation Authority, Kingdom of Saudi Arabia (12996-iau-2023-TAUR-3-1-HW-) and the National Eye Institute (R01EY035717).

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