“Most babies born with a congenital malformation die within the first year of life and although many mutations responsible for congenital syndromes have been identified the underlying mechanism responsible for these malformations remains under studied.
We showed that heterozygous mutations in the core component of the spliceosome gene SNRPB are responsible for Cerebrocostomandibular Syndrome (CCMS). CCMS patients carry mutations that increase inclusion of a pretermination containing (PTC) exon (AE2) important for regulating Snrpb levels. These patients present with craniofacial and rib defects at birth and 50% die within the first month.
Our goal is to uncover the requirement for SNRPB in the paraxial mesoderm, the precursor of the ribs and vertebrae. We generated several mutant mouse lines with mutation in Snrpb that develop abnormalities like those seen in CCMS. Using RNAseq we identified candidate genes important for ribs and vertebrae development. Our hypothesis is that reduced levels of RA, a vitamin A derivative, and mis-splicing of the chromatin modifier, Setd5, in presomitic mesoderm are responsible for vertebrae and rib defects in Snrpbtmx mutant embryos.
We Aim to uncover the contribution of (1) increase levels of the RA catabolizing gene Cyp26a1 , and (2) reveal the contribution of mis-splicing of Setd5 to vertebral and rib defects in Snrpb mutant embryos; and (3) to evaluate the requirement of Snrpb in paraxial mesoderm for normal vertebrae and rib development. Our work will uncover pathways shared with other spliceosomopathies syndromes. Though a rare syndrome, rib and vertebrae abnormalities found in CCMS are also found in other poorly studied congenital malformations. Our mechanistic work will help in the development of treatments that can prevent or reduce the incidence of these defects in the population”
Project Title: Germline DNMT3A loss-of-function alters histone H3K27 methylation and causes neuronal impairments
Principal Investigator: Serge McGraw (Centre hospitalier universitaire Sainte-Justine).
“Tatton-Brown-Rahman Syndrome (TBRS) is a rare genetic disorder caused by mutations in the DNMT3A gene. People with TBRS often grow taller, heavier, and have a larger head size. They may have learning difficulties, low muscle tone, heart issues, behavioral challenges, mental health problems, and autism-like traits. Symptoms can vary widely. Many TBRS disabilities are similar to those in other overgrowth and intellectual syndromes, like Weaver, Cohen-Gibson, and Imagawa-Matsumoto, which may share common mechanisms affecting brain cell growth and function.
The DNMT3A enzyme is important for DNA methylation, a process that controls gene activity by adding chemical tags to DNA. In TBRS, changes in the DNMT3A gene disrupt this process, leading to abnormal gene regulation and causing the syndrome’s symptoms. While we know DNMT3A’s role, how it leads to the neurodevelopmental problems in TBRS is still unclear.
To address this, we created a new patient-derived model by turning cells from people with TBRS into induced pluripotent stem cells (iPSCs), which can become any cell type, including 3D brain organoids. These iPSCs help us study how DNMT3A mutations affect DNA methylation and brain cells. We also developed a TBRS mouse model to better understand how the disorder impacts brain cell connections and function, offering valuable insights into the neurological causes of TBRS.
Our research has the potential to not only deepen our understanding of the molecular mechanisms behind TBRS but also provide insights into other related overgrowth and intellectual disability syndromes. By studying how DNMT3A mutations affect brain development and function, we can uncover common pathways that may be shared with other disorder syndromes. This knowledge could pave the way for new, targeted treatments for TBRS and similar conditions, ultimately improving the quality of life for individuals affected by these rare genetic disorders.“
