Related Experiment Video

Updated: May 9, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
00:06

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

13.5K

Pleiotropic effects of MORC2 derive from its epigenetic signature

Fatemeh Peymani1,2, Tomohiro Ebihara2, Dmitrii Smirnov1,2

  • 1Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany.

Brain : a Journal of Neurology
|April 30, 2025
PubMed

Insights

Pathogenic variants in MORC2 cause a DNA methylation signature, leading to gene repression and varied symptoms in patients. This epigenetic change explains the diverse clinical outcomes in MORC2-related disorders.

Area of Science:

  • Genetics
  • Epigenetics
  • Molecular Biology

Background:

  • Heterozygous missense mutations in MORC2 are linked to diverse clinical conditions, from early neurodevelopmental issues to late-onset neuropathies.
  • The underlying mechanisms for the wide range of symptoms and pleiotropic effects of MORC2 mutations remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms behind the phenotypic heterogeneity in MORC2-related disorders.
  • To identify a potential epigenetic link explaining the pleiotropic effects of MORC2 mutations.

Main Methods:

  • Analysis of DNA methylation, transcriptomes, proteomes, and clinical phenotypes in 53 patients with MORC2 mutations.
  • Utilized multi-omics data to correlate molecular changes with clinical manifestations.

Main Results:

  • Identified a universal MORC2-specific DNA methylation episignature across all phenotypes and tissues.
  • Observed DNA hypermethylation in promoter regions, leading to transcriptional repression and a distinct RNA signature.
  • Downregulation of ERCC8, NDUFAF2, and FKTN correlated with specific clinical features like Leigh syndrome and dysmorphic features.

Conclusions:

  • Pathogenic MORC2 variants induce a specific DNA methylation episignature, explaining the pleiotropy and phenotypic heterogeneity.
  • Epigenetic variations, particularly DNA methylation changes, are proposed as a key mechanism for pleiotropy in MORC2 disorders and potentially other Mendelian conditions.
Keywords:
CMTLeigh syndromeMORC2episignaturemulti-omicspleiotropy

More Related Videos

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information09:37

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Published on: August 15, 2019

9.6K
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease09:34

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Published on: April 4, 2018

33.4K

Related Concept Videos

Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
6.7K
Pleiotropy01:33

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
37.8K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
2.9K
Genomic Imprinting and Inheritance02:30

Genomic Imprinting and Inheritance

Diploid organisms inherit genetic material through chromosomes from both parents. Copies of the same gene are known as alleles. In most cases, both alleles are simultaneously expressed and allow various cellular processes to function optimally. If one of the alleles is missing or mutated, the expression of the other allele can compensate; however, this is not true for all genes.
The expression of some genes depends on which parent passed the gene to the offspring, through a phenomenon known as...
32.8K
Position-effect Variegation02:32

Position-effect Variegation

In 1928, a German botanist Emil Heitz observed the moss nuclei with a DNA binding dye. He observed that while some chromatin regions decondense and spread out in the interphase nucleus, others do not. He termed them euchromatin and heterochromatin, respectively. He proposed that the heterochromatin regions reflect a functionally inactive state of the genome. It was later confirmed that heterochromatin is transcriptionally repressed, and euchromatin is transcriptionally active chromatin.
6.2K
Epistasis01:39

Epistasis

In addition to multiple alleles at the same locus influencing traits, numerous genes or alleles at different locations may interact and influence phenotypes in a phenomenon called epistasis. For example, rabbit fur can be black or brown depending on whether the animal is homozygous dominant or heterozygous at a TYRP1 locus. However, if the rabbit is also homozygous recessive at a locus on the tyrosinase gene (TYR), it will have an unshaded coat that appears white, regardless of its TYRP1...
43.4K