Hypomethylation of Wnt Signaling Regulator Genes in Developmental Language Disorder

Abstract

Background: Developmental language disorder (DLD) is a neurodevelopmental disorder. Considering the pivotal role of epigenetics in neurodevelopment, we examined any altered DNA methylation between DLD and control subjects. Materials & methods: We looked into genome-wide methylation differences between DLD and control groups. The findings were validated by quantitative PCR (qPCR). Results: In the DLD group, differential methylation of CpG sites was observed in the Wnt signaling regulator genes APCDD1, AMOTL1, LRP5, MARK2, TMEM64, TRABD2B, VEPH1 and WNT2B. Hypomethylation of APCDD1, LRP5 and WNT2B was confirmed by qPCR. Conclusion: This is the first report associating Wnt signaling with DLD. The findings are relevant in the light of the essential role of Wnt in myelination, and of the altered myelination in DLD.

Plain language summary

Developmental language disorder (DLD), previously called specific language impairment, is a neurodevelopmental disorder affecting approximately 7% of school-age children. Affected children fail to develop normal speech and language skills; this is a major public health concern as it adversely impacts their communication, academic and social skills. Human brain development is complex, and the accurate temporal and spatial regulation of the expression of multiple genes is essential for proper brain development. Epigenetic factors such as DNA methylation can modulate gene expression without altering the DNA sequence and are considered key regulators of the expression of genes involved in neurodevelopment. We examined any genome-wide methylation differences between children with DLD and control subjects. The findings were validated by real-time qPCR. The DLD group showed differential methylation of CpG sites in several Wnt signaling regulator genes (APCDD1, AMOTL1, LRP5, MARK2, TMEM64, TRABD2B, VEPH1, WNT2B) compared with the control group. Among these, hypomethylation of APCDD1, LRP5 and WNT2B was confirmed by qPCR. This is the first report associating Wnt signaling with DLD. The findings are relevant in the light of the essential role of Wnt in neuronal myelination and the altered myelination in DLD revealed by magnetic resonance imaging.

Tweetable abstract

Altered neuronal myelination is observed in developmental language disorder (DLD). Wnt signaling has a crucial role in myelination. Altered DNA methylation of Wnt signaling regulator genes could be a potential contributing factor to DLD.

Keywords::

• developmental language disorder
• epigenetics
• methylation
• specific language impairment
• Wnt signaling

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2023-0345

Author contributions

All authors made substantial contributions to the conception/design of the work and/or the acquisition, analysis, or interpretation of data; contributed to drafting the work and/or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors thank the staff and students of Department of Audiology and Speech Language Pathology (ASLP), Institute for Communicative and Cognitive Neurosciences (ICCONS), Shoranur, Palakkad, Kerala, India for carrying out the speech and language evaluations of the study participants.

Financial disclosure

This work was supported by the Science and Engineering Research Board (SERB), a statutory body of the Department of Science and Technology, Govt. of India, under Core Research Grant (EMR/2017/001481). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study was approved by the Institutional Ethics Committee (IEC) of Institute for Communicative and Cognitive Neurosciences (ICCONS) duly constituted as per the guidelines of the Indian Council of Medical Research (ICMR). Written informed consent was obtained from the parents of all of the participants.

Data sharing statement

The data from methylome analysis, both raw data and processed data, have been submitted to ArrayExpress (www.ebi.ac.uk/fg/annotare/); the accession number is E-MTAB-13583.

Additional information

Funding

This work was supported by the Science and Engineering Research Board (SERB), a statutory body of the Department of Science and Technology, Govt. of India, under Core Research Grant (EMR/2017/001481). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.