Inherited Retinal Diseases |
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Background
Inherited retinal diseases (IRD) are a major cause of early-onset blindness, affecting the welfare of over two million individuals worldwide. They cover a broad spectrum of monogenic diseases characterized by a tremendous clinical and genetic heterogeneity. So far, over 260 disease genes have been identified, for which mutations in the coding regions explain up to 50-70% of cases. Recent whole exome and genome sequencing studies did not reveal many new disease genes, strengthening the hypothesis that the missing mutations of IRD reside in noncoding, regulatory regions of known disease genes. Importantly, the identification of the genetic defect and the underlying biological pathway is a prerequisite for gene therapy, which is now entering the clinic for several IRD subtypes. Mission Our mission is to unravel the genetic basis of IRD in order to enhance molecular diagnoses, to understand mechanisms of disease and to pave the way for gene therapy. Specifically, we aim:
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Strategy
To shed light on IRD-associated missing heritability we map the cis-regulatory landscape of human retina by chromatin conformation profiling and reveal disease-associated variants in retina-specific cis-regulatory elements by targeted locus resequencing and whole genome sequencing. As the interpretation of variants of uncertain significance in known IRD genes and variants in novel IRD genes remains challenging, we set up CRISPR/Cas9-based workflows in Xenopus tropicalis to assess the effect of these variants. Finally, we develop new therapeutic approaches for deep-intronic and regulatory mutations using antisense oligonucleotides, which are evaluated in cellular models. |
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Developmental Disorders |
Background
Human genetic disorders are classically caused by mutations in genes, representing the coding portion of the genome. However, many other mechanisms can impair normal gene function, and potentially lead to disease. Some genes, especially those that play a role in development, need a strict expression in time, place and quantity. The instructions for correct expression can be found in the so-called regulatory code of the genome, which is yet far from deciphered. Studies of specific human genetic disorders have been very useful to uncover disease-causing disruptions of the regulatory code, also called “cis-ruptions”.
Mission
Our general aim is to identify and functionally validate novel cis-ruptions in several developmental disorders - such as BPES (FOXL2 region) - for which a unique patient collection is available. This project will contribute to cracking the regulatory code in our genome in relevant tissues, and new cis-ruption mechanisms may serve as a model for other genetic, acquired and complex disorders.
Strategy
Newly identified cis-ruptions, such as genetic changes in highly conserved non-coding elements or putative enhancer elements, will be validated using in vitro assays (reporter assays; chromosome conformation studies) and in vivo assays (zebrafish, mouse). An extensive validation of these genetic defects is of utmost importance before interpreting them in a clinical context.
Human genetic disorders are classically caused by mutations in genes, representing the coding portion of the genome. However, many other mechanisms can impair normal gene function, and potentially lead to disease. Some genes, especially those that play a role in development, need a strict expression in time, place and quantity. The instructions for correct expression can be found in the so-called regulatory code of the genome, which is yet far from deciphered. Studies of specific human genetic disorders have been very useful to uncover disease-causing disruptions of the regulatory code, also called “cis-ruptions”.
Mission
Our general aim is to identify and functionally validate novel cis-ruptions in several developmental disorders - such as BPES (FOXL2 region) - for which a unique patient collection is available. This project will contribute to cracking the regulatory code in our genome in relevant tissues, and new cis-ruption mechanisms may serve as a model for other genetic, acquired and complex disorders.
Strategy
Newly identified cis-ruptions, such as genetic changes in highly conserved non-coding elements or putative enhancer elements, will be validated using in vitro assays (reporter assays; chromosome conformation studies) and in vivo assays (zebrafish, mouse). An extensive validation of these genetic defects is of utmost importance before interpreting them in a clinical context.
Disorders of Sex Development |
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Background
Generally, we perceive our biological sex as a binary characteristic. Disorders of sex development (DSD) – rare conditions in which the development of chromosomal, gonadal or anatomical sex is atypical – clearly demonstrate that our biological sex should rather be seen as a spectrum, in which each position between male and female is possible. DSDs affect approximately one in 4,500 newborns, and when milder forms like isolated micropenis or hypospadias are taken into account no less than one in 200 children are affected. Over the years several important genes involved in the pathogenesis of these conditions have been identified, however the underlying molecular defect is known in only ~40% of cases. The identification of the causal gene can help the patients and their parents to understand and accept their situation and it enables genetic counseling for the family. Additionally, increased knowledge on the pathways behind these rare conditions can also learn us something about the pathogenic mechanisms behind related, more prevalent conditions like male infertility and primary ovarian insufficiency (POI). Mission Our main goal is to unravel the molecular mechanisms behind DSDs and related conditions like POI. Strategy We apply state-of-the-art genomic technologies (WES, WGS, RNA-seq), cellular model systems, animal models and bioinformatics to elucidate the molecular mechanisms behind DSDs and related conditions. |