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Gabel Lab identifies molecular links between Sotos and Tatton Brown Rahman Syndromes

Nicole Hamagami and Dennis Wu
Co-first authors of the paper, Nicole Hamagami and Dennis Wu

Sotos Syndrome and Tatton Brown Rahman Syndrome bear striking similarities, so much so that patients with one have been misdiagnosed as having the other. Both rare diseases cause large stature and head size, also known as overgrowth, distinct facial features, a high prevelance of autism, and intellectual disability. But the two diseases have different genetic origins: Sotos is caused by variants in the NSD1 gene while TBRS involves mutations in the DNMT3A gene. Researchers have now made progress in understanding why Sotos and TBRS are so alike. The laboratory of Harrison Gabel, PhD, Associate Professor in the Department of Neuroscience at Washington University School of Medicine, reports in Molecular Cell that mutations in NSD1 and DNMT3A in mouse models lead to convergent shifts in the activity of genes within neurons.

“We saw overwhelming overlap in concordantly upregulated genes,” said Nicole Hamagami, the co-first author of the paper. “It was pretty exciting to see. It suggests there’s this overarching genetic de-repression that’s happening between these two diseases,” added Hamagami, who is a graduate student in the Gabel Lab in the medical scientist training program.

“Our study points to neuronal DNA methylation as a convergence point in TBRS, Sotos syndrome and likely additional disorders,” said Gabel. “We think this serves as a model for how to decode distinct genetic diseases with overlapping pathology.”

NSD1 and DNMT3Aare enzymes involved in gene regulation through methylation. NSD1 deposits methyl groups onto histones—specifically, the histone H3K36—and DNMT3A adds methyl groups to DNA, including the brain-specific methylation of CA dinucleotides (mCA) in the genome. “The deposition and readout of the mCA mark is really important for regulation of neuronal genes and critical for neuronal function,” said Hamagami, which explains why mutations in DNMT3A can lead to neurodevelopmental disorders. The question she was after was whether the substrates of NSD1 and DNMT3A are related.

A lot of neurodevelopmental disorder models and autism spectrum disorder models tend to have subtle gene effects, but we think the accumulation of these subtle gene effects is what’s contributing to the disease.

Nicole Hamagami

Hamagami, together with her co-first author Dennis Wu, another student in the lab, and colleagues, first set out to determine how the pattern of mCA is established across the genome. Studies outside the nervous system have shown that H3K36 methylation recruits DNMT3A to methylate CG dinucleotides in the genome. To see if the same is true for mCA in the brain, the team compared H3K36 methylation patterns in the cerebral cortex of young mice and found that it mirrored later mCA patterns in the genome of neurons. They then disrupted the function of NSD1 and found that in regions of the genome where H3K36 methylation was perturbed, mCA patterns were similarly altered.

“We see epigenetic dysregulation occurring,” said Hamagami. “The ultimate question is, given that we see shared clinical phenotypes across TBRS and Sotos, can we explain that overlap at the molecular level and observe transcriptional disruption across different disease models?”

To answer this question, the team turned to a TBRS mouse model the Gabel Lab had already developed. They also created a mouse with NSD1 knocked out in the brain. Comparing effects on gene expression in the mice’s brains, they found parallel upregulation in genes important for neuronal development and maturation processes. “A lot of neurodevelopmental disorder models and autism spectrum disorder models tend to have subtle gene effects, but we think the accumulation of these subtle gene effects is what’s contributing to the disease,” said Hamagami.

She said that identifying points of convergence in rare diseases is important for developing therapeutics that could treat multiple disorders. Presently, there are no treatments for Sotos or TBRS.

Learn more about the Gabel Lab »

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