Presentation Notes Mutations in the TWIST1 gene are associated with Saethre-Chotzen syndrome, breast cancer, and Szary

Syndrome. SaethreChotzen syndrome (SCS) is a rare congenital disorder associated with craniosynostosis (premature closure of one or more of the sutures between the bones of the skull). (A suture is a fairly rigid joint between two or more hard elements of an organism, with or without significant overlap of the elements.). This affects the shape of the head and face, resulting in a cone-shaped head and an asymmetrical face Szary's disease (often called Szary syndrome) is a type of cutaneous lymphoma that was first described by Albert Szary. The affected cells are Tcells that have pathological quantities of mucopolysaccharides. Szary's disease is sometimes considered a late stage of mycosis fungoides with lymphadenopathy. There are currently no known causes of Szary's disease. Lymphoma is a type of blood cancer that occurs when B or T lymphocytes, the white blood cells that form a part of the immune system and help protect the body from infection and disease, divide faster than normal cells or live longer than they are supposed to. Lymphoma may develop in the lymph nodes, spleen, bone marrow, blood or other organs and eventually they form a tumor. Thus, Twist1 plays an essential role in cancer metastasis; hence targeting Twist has a great promise as a cancer therapeutic. In molecular biology and bioinformatics, the consensus sequence is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It represents the results of a multiple sequence alignments in which related sequences are compared to each other and similar sequence motifs are calculated. Since the regulatory function of these sequences is important, they are thought to be conserved across long periods of evolution. Evolutionary relatedness can be estimated by the amount of conservation of these sites. A protein binding site, represented by a consensus sequence, may be a short sequence of nucleotides which is found several times in the genome and is thought to play the same role in its different locations. For example, many transcription factors recognize particular patterns in the promoters of the genes they regulate. Sequence alignment aims to match homologous characters, nucleotides or amino acids that are descended from a common ancestor. This is complicated by base substitutions that decrease similarity between sequences over evolutionary time and insertions and deletions that add and remove sequence in different evolutionary lineages. Sequence similarities serve as evidence for structural and functional conservation, as well as of evolutionary relationships between the sequences. Consequently, comparative analysis is the primary means by which functional elements are identified. Some deletions of highly conserved sequences in humans and other organisms have been suggested to be a potential cause of the anatomical and behavioral differences between humans and other mammals. (McLean, Cory Y.; et al. (10 March 2011)). Orthologues are one of two or more homologous gene sequences found in different species. Homologous: having the same relation, relative position, or structure, in particular. The TWIST1 gene provides instructions for making a protein that plays an important role in early development. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and controls the activity of particular genes. Specifically, the TWIST1 protein is part of a large protein family called basic helix-loop-helix (bHLH) transcription factors. Each of these proteins includes a region called the bHLH domain, which determines the protein's 3-dimensional shape and enables it to target particular sequences of DNA. The bHLH family of transcription factors helps regulate the development of many organs and tissues before birth. A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other.

During embryonic development, the TWIST1 protein is essential for the formation of cells that give rise to bone, muscle, and other tissues in the head and face. The TWIST1 protein also plays a role in the early development of the limbs.

How are changes in the TWIST1 gene related to health conditions? Saethre-Chotzen syndrome - caused by mutations in the TWIST1 gene

More than 80 mutations in the TWIST1 gene have been identified in people with Saethre-Chotzen syndrome. Some of these mutations change single protein building blocks (amino acids) in the TWIST1 protein, while others delete or insert genetic material in the gene. In some cases, this condition is caused by chromosomal abnormalities (translocations or deletions) involving the region of chromosome 7 that contains the TWIST1 gene. TWIST1 mutations prevent one copy of the gene in each cell from producing any functional protein. A shortage of functional TWIST1 protein affects the development and maturation of cells in the skull, face, and limbs. These abnormalities underlie the signs and symptoms of Saethre-Chotzen syndrome, although it is unclear exactly how a shortage of the TWIST1 protein causes specific features such as the premature fusion of certain skull bones. other disorders - caused by mutations in the TWIST1 gene TWIST1 mutations have also been found in several people with isolated craniosynostosis, which is a premature fusion of certain skull bones that occurs without the other signs and symptoms of SaethreChotzen syndrome. These mutations occur near the end of the gene in a region known as the TWIST box domain. This domain enables the TWIST1 protein to bind to and regulate a gene called RUNX2, which is a critical regulator of bone formation. Researchers believe that mutations in the TWIST box domain prevent the TWIST1 protein from effectively controlling the activity of the RUNX2 gene, which disrupts the normal pattern of bone formation in the skull and leads to craniosynostosis. Where is the TWIST1 gene located? Cytogenetic Location: 7p21.2 Molecular Location on chromosome 7: base pairs 19,039,314 to 19,157,294

The TWIST1 gene is located on the short (p) arm of chromosome 7 at position 21.2. More precisely, the TWIST1 gene is located from base pair 19,039,314 to base pair 19,157,294 on chromosome 7. (http://ghr.nlm.nih.gov/gene/TWIST1) The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. Placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some non-mammals with varying levels of development.