Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

A novel genomic mutation in ADNP leading to intellectual disability

European Journal of Human Genetics volume 31, pages 851–852 (2023)Cite this article

Subjects

The Original Article was published on 24 February 2023

Performing genome sequencing for genetic diagnosis of a young girl, Mathieu Georget et al. [1] discovered a de novo, non-inherited, intragenic inversion in the gene encoding activity-dependent neuroprotective protein (ADNP) [2, 3]. Clinically, the girl exhibited global developmental delay that was predominated by language impairment (speech onset at 21 months), recurrent infections, visual impairment, constipation and difficulties in behavioral and social interaction [1]. This ADNP syndrome individual (ORPHA:404448) joins hundreds of cases globally. However, previously described cases, exhibiting similar phenotypic characteristics to the currently described child, were mostly characterized by STOP or frameshift STOP, high impact ADNP truncating mutations. Interestingly, we recently described another novel case of a de novo missense mutation resulting in ADNP containing NAPVISPQE instead of NAPVSIPQQ, revealing one amino acid change, encompassing a highly important ADNP site (drug candidate NAP/davunetide), in a young boy presenting developmental hypotonia, possibly associated with inflammation affecting food intake in early life coupled with fear of peer interactions [4]. Together, these studies strongly emphasize the significance of functional ADNP during early development. Georget’s new findings [1] further highlight the requirement for whole genome DNA sequencing toward better diagnosis, which will lead to improved future treatment modalities. This approach could also include enhanced focus on lead genes, essential for brain formation, like ADNP.

Georget et al. further addressed constitutive Alu sequences with high homology at both breakpoints in reversed orientation of the reference genome, and hypothesized that Alu-mediated non-allelic-homologous recombination was responsible for the newly discovered ADNP gene rearrangement [1]. Bearing in mind that Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability, these findings have consequences beyond the described case. For example, methylation alterations were observed in Alu sequences in heterogeneous autism spectrum disorder, and were associated with altered autism gene expression patterns [5]. Together, Alu and related sequences associated with genomic instability are proposed as future epigenomic biomarkers for autism spectrum disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Georget M, Lejeune E, Buratti J, Servant E, le Guern E, Heron D, et al. Loss of function of ADNP by an intragenic inversion. European journal of human genetics: EJHG. 2023. Available from: http://www.ncbi.nlm.nih.gov/pubmed/36828924.

  2. Zamostiano R, Pinhasov A, Gelber E, Steingart RA, Seroussi E, Giladi E, et al. Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem. 2001;276:708–14. http://www.ncbi.nlm.nih.gov/pubmed/11013255.

    Article  CAS  PubMed  Google Scholar 

  3. Bassan M, Zamostiano R, Davidson A, Pinhasov A, Giladi E, Perl O, et al. Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. 1999;72:1283–93. http://www.ncbi.nlm.nih.gov/pubmed/10037502.

    Article  CAS  PubMed  Google Scholar 

  4. Gozes I, Shazman S A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity-dependent neuroprotective protein (ADNP) causes a mild developmental syndrome. Eur J Neurosci. 2023. Available from: http://www.ncbi.nlm.nih.gov/pubmed/36669790.

  5. Saeliw T, Permpoon T, Iadsee N, Tencomnao T, Hu VW, Sarachana T, et al. LINE-1 and Alu methylation signatures in autism spectrum disorder and their associations with the expression of autism-related genes. Sci Rep. 2022;12:13970. http://www.ncbi.nlm.nih.gov/pubmed/35978033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ivashko-Pachima Y, Hadar A, Grigg I, Korenkova V, Kapitansky O, Karmon G, et al. Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: mutated ADNP cytoskeletal impairments and repair as a case study. Mol Psychiatry. 2021;26:1619–33. http://www.ncbi.nlm.nih.gov/pubmed/31664177.

    Article  CAS  PubMed  Google Scholar 

  7. Ji N, Wu CG, Wang XD, Song ZX, Wu PY, Liu X, et al. Anti-aging effects of Alu antisense RNA on human fibroblast senescence through the MEK-ERK pathway mediated by KIF15. Curr Med Sci. 2023;43:35–47. http://www.ncbi.nlm.nih.gov/pubmed/36808398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ivashko-Pachima Y, Ganaiem M, Ben-Horin-Hazak I, Lobyntseva A, Bellaiche N, Fischer I, et al. SH3- and actin-binding domains connect ADNP and SHANK3, revealing a fundamental shared mechanism underlying autism. Mol Psychiatry. 2022;27:3316–27. http://www.ncbi.nlm.nih.gov/pubmed/35538192.

    Article  CAS  PubMed  Google Scholar 

  9. Karmon G, Sragovich S, Hacohen-Kleiman G, Ben-Horin-Hazak I, Kasparek P, Schuster B, et al. Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and Tau pathologies. Biol Psychiatry. 2022;92:81–95. http://www.ncbi.nlm.nih.gov/pubmed/34865853.

    Article  CAS  PubMed  Google Scholar 

  10. Hacohen-Kleiman G, Sragovich S, Karmon G, Gao AYL, Grigg I, Pasmanik-Chor M, et al. Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome. J Clin Investig. 2018;128:4956–69. http://www.ncbi.nlm.nih.gov/pubmed/30106381.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was partially supported by grants to IG from the European Research Area Network (ERA-NET) Neuron ADNPinMED, Drs. Ronith and Armand Stemmer (French Friends of Tel Aviv University), Holly and Jonathan Strelzik (American Friends of Tel Aviv University) and Anne and Alex Cohen (Canadian Friends of Tel Aviv University). IG is Director of the Elton Laboratory for Molecular Neuroendocrinology and the former first incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors.

Author information

Authors and Affiliations

  1. Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel

    Illana Gozes

Authors
  1. Illana Gozes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

IG conceptualized and wrote this commentary.

Corresponding author

Correspondence to Illana Gozes.

Ethics declarations

Competing interests

The diagnostic use of ADNP levels and the clinical use of davunetide are under patent protection (IG, inventor).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gozes, I. A novel genomic mutation in ADNP leading to intellectual disability. Eur J Hum Genet 31, 851–852 (2023). https://doi.org/10.1038/s41431-023-01387-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41431-023-01387-9

This article is cited by

Search

Advanced search

Quick links