Arhinia, Choanal Atresia, and Microphthalmia

A fundamental discovery about a driver of healthy development in embryos could rewrite our understanding of what can be inherited from our parents and how their life experiences may shape us. A fundamental discovery about a driver of healthy development in embryos could rewrite our understanding of what can be inherited from our parents and how their life experiences may shape us. The new research suggests that epigenetic information, which sits on top of DNA and is normally reset between generations, is more frequently carried from mother to offspring than previously thought. The study, led by researchers from WEHI (Melbourne, Australia), significantly broadens our understanding of which genes have epigenetic information passed from mother to child and which proteins are important for controlling this unusual process. Epigenetics is a rapidly growing field of science that investigates how our genes are switched on and off to allow one set of genetic instructions to create hundreds of different cell types in our body. Epigenetic changes can be influenced by environmental variations such as our diet, but these changes do not alter DNA and are normally not passed from parent to offspring. While a tiny group of 'imprinted' genes can carry epigenetic information across generations, until now, very few other genes have been shown to be influenced by the mother's epigenetic state. The new research reveals that the supply of a specific protein in the mother's egg can affect the genes that drive skeletal patterning of offspring. Chief investigator Professor Marnie Blewitt said the findings initially left the team surprised. "It took us a while to process because our discovery was unexpected," Professor Blewitt, Joint Head of the Epigenetics and Development Division at WEHI, said. "Knowing that epigenetic information from the mother can have effects with life-long consequences for body patterning is exciting, as it suggests this is happening far more than we ever thought. "It could open a Pandora's box as to what other epigenetic information is being inherited." The study, led by WEHI in collaboration with Associate Professor Edwina McGlinn from Monash University and The Australian Regenerative Medicine Institute, is published in Nature Communications. The new research focused on the protein SMCHD1, an epigenetic regulator discovered by Professor Blewitt in 2008, and Hox genes, which are critical for normal skeletal development. Hox genes control the identity of each vertebra during embryonic development in mammals, while the epigenetic regulator prevents these genes from being activated too soon. In this study, the researchers discovered that the amount of SMCHD1 in the mother's egg affects the activity of Hox genes and influences the patterning of the embryo. Without maternal SMCHD1 in the egg, offspring were born with altered skeletal structures. First author and PhD researcher Natalia Benetti said this was clear evidence that epigenetic information had been inherited from the mother, rather than just blueprint genetic information. "While we have more than 20,000 genes in our genome, only that rare subset of about 150 imprinted genes and very few others have been shown to carry epigenetic information from one generation to another," Benetti said. "Knowing this is also happening to a set of essential genes that have been evolutionarily conserved from flies through to humans is fascinating." The research showed that SMCHD1 in the egg, which only persists for two days after conception, has a life-long impact. Variants in SMCHD1 are linked to developmental disorder Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy (FSHD), a form of muscular dystrophy. The researchers say their findings could have implications for women with SMCHD1 variants and their children in the future. A drug discovery effort at WEHI is currently leveraging the SMCHD1 knowledge established by the team to design novel therapies to treat developmental disorders, such as Prader Willi Syndrome and the degenerative disorder FSHD. The research was supported by the NHMRC, a Bellberry-Viertel Senior Medical Research fellowship, the Victorian Government and the Australian Government. WEHI authors: Natalia Benetti, Quentin Gouil, Andres Tapia del Fierro, Tamara Beck, Kelsey Breslin, Andrew Keniry, Marnie Blewitt.

Scientists have discovered a new way to interpret unsolved Mendelian diseases -- diseases inherited from either parent due to gene mutations in the developing egg or sperm -- through studying the inheritance of a protein known as SMCHD1 which is coded by the SMCHD1 gene. The development of an embryo is a well-orchestrated string of processes, ensuring correct formation and positioning of vital organs of the growing organism. At the molecular level, these processes are controlled in a precise manner by switching on or off specific factors such as genes or proteins. Any errors in these processes could result in physical defects or disease in the newborn organism. A team of scientists from the National University of Singapore (NUS) led by Assistant Professor Xue Shifeng from the Department of Biological Sciences has discovered a new way to interpret unsolved Mendelian diseases -- diseases inherited from either parent due to gene mutations in the developing egg or sperm -- through studying the inheritance of a protein known as SMCHD1 which is coded by the SMCHD1 gene. Mutations in the SMCHD1 gene can cause diseases such as facioscapulohumeral muscular dystrophy (FSHD) which is a muscle degenerative disorder, and Bosma arhinia microphthalmia syndrome (BAMS) which causes abnormalities of the nose and eyes. The researchers found that SMCHD1 from mothers controls the expression of a group of genes in offspring, known as the HOX genes, which determines the position of body parts in an embryo along the axis from its head to tail. The researchers also found that the inactivation of SMCHD1 in female zebrafish results in alterations to HOX gene expression leading to skeletal defects in their offspring. The study led by NUS researchers, in collaboration with A*STAR, Yale-NUS and Aix-Marseille University, was published in Nature Communicationson 23 June 2022. Inheritance of mother's genes and structural defects In mammals, SMCHD1 plays a key role in X-inactivation in females, a process where one of the copies of the X chromosome is randomly selected and disabled. This makes it challenging to study the role of the SMCHD1 gene inherited from mothers because inactivating the SMCHD1 gene is lethal for female mammals. The research team decided to use zebrafish, a vertebrate commonly used as a model organism in biomedical research, to circumvent this issue. Zebrafish lack X-inactivation, allowing the team to study the role of the SMCHD1 gene inherited from mothers. The researchers inactivated the SMCHD1 gene in zebrafish to study how it will affect gene expression and structural development in zebrafish offspring. NUS scientists observed that SMCHD1 protein is placed into the egg by the mother. The inactivation of the SMCHD1 gene in female zebrafish caused alterations in HOX gene expression in their fertilised eggs. HOX genes play an important role in ensuring the specific patterns and identities of different body parts in the baby. The loss of the SMCHD1 gene resulted in premature activation of HOX genes resulting in skeletal patterning defects in the zebrafish offspring. Asst Prof Xue and her team demonstrated a new concept that gene products such as proteins from the mother's egg can control gene expression occurring in the developing embryo. Factors that control gene expression produced by the mother in the developing egg can set up the conditions for proper gene activation after the egg is fertilised with a sperm. Through further lab studies, the team found that the same principle applied to mammals. Interpreting unsolved genetic diseases The results of the study could change the way unsolved Mendelian diseases are interpreted. Based on this study, some genetic abnormalities in parents could manifest in their children, opening possibilities of explaining birth defects seen in children by examining the genetic make-up of their parents. "When we think about genetic diseases, we usually think that a mutation in the patient caused the disease. In our study, we found using zebrafish, the abnormalities in the offspring are not caused by a genetic mutation in the individual but in its mother. This will change how we think about unsolved inherited diseases," said Asst Prof Xue. Future research Following their current study, the researchers hope to continue exploring how, at the molecular level, maternal genes control embryo gene expression after birth. "We want to understand, molecularly, what marks are left by the maternal SMCHD1 gene on the offspring's genome that will affect the embryo. We are also interested in studying the SMCHD1 protein, its mutations that are involved in different diseases, as well as how it works," shared Asst Prof Xue.