Some genetic mutations may offer protection against developmental disorders

Tel Aviv University researchers have made a remarkable discovery that could revolutionize our understanding of genetic mutations and their role in brain development. The study, published today in Genomic Psychiatry, reveals that not all genetic mutations are harmful – some may actually offer protection against developmental disorders.

Led by Professor Illana Gozes, Director, The Elton Laboratory for Molecular Neuroendocrinology, the research team identified a protective inherited mutation in the Activity-Dependent Neuroprotective Protein (ADNP) gene. This finding challenges the traditional view that genetic mutations in ADNP invariably lead to developmental challenges.

I was struck by how this particular mutation actually enhanced certain protein interactions, potentially offering protection against developmental disorders. This discovery opens up entirely new perspectives on how we view genetic variations and their impact on brain development."

Professor Illana Gozes, Director, The Elton Laboratory for Molecular Neuroendocrinology

The study focused on a unique case where a mother carrying an ADNP mutation showed above-average adaptive behavior, while her child, inheriting both this protective mutation and a second variant, demonstrated better outcomes than typically seen in similar cases.

Key findings include:

• The protective mutation (ADNP_Glu931Glyfs*12) creates an additional protein interaction site

• This enhancement leads to stronger cellular connections and improved protein function

• The discovery suggests potential new therapeutic approaches for neurodevelopmental disorders

What makes this finding particularly intriguing is how it might influence our approach to genetic therapy. Could other seemingly harmful mutations harbor unexpected benefits? How might this knowledge be applied to develop more effective treatments?

Dr. Shula Shazman, a co-author of the study, notes that their computational modeling revealed how this protective mutation strengthens crucial cellular processes. This insight raises interesting questions about the potential for identifying similar protective mutations in other genes associated with neurodevelopmental disorders.

The research has immediate implications for how we understand and treat ADNP syndrome, a rare genetic condition affecting brain development. More broadly, it challenges us to reconsider our assumptions about genetic mutations in neurodevelopmental disorders.

The study employed advanced computational modeling alongside clinical observations, led by the psychiatrist, Prof. Joseph Levine. The results demonstrated how modern bioinformatics can reveal unexpected benefits in genetic variations previously considered purely detrimental.

Looking ahead, this research opens several compelling avenues for further investigation: How common are protective mutations in other neurological conditions? Could this discovery lead to new therapeutic strategies for related disorders?

From bench to bedside, Professor Illana Gozes further serves as Vice President for Drug Development at Exonavis Therapeutics, developing the investigational drug davunetide, a neuroprotective fragment of ADNP, for the treatment of ADNP syndrome and related neurodevelopmental/ neurodegenerative disorders. Indeed, her original discoveries providing the basis for davunetide also stemmed from structure-function relations toward new horizons,