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Cutis laxa: current research Zsolt Urban, Ph.D. Department of Human Genetics Graduate School of Public Health University of Pittsburgh Website: www.hgen.pitt.edu/projects/cutislaxa E-mail: [email protected] Who am I and why am I here? • Michelle Morrow, PhD • Former neuroscience researcher • Half cutis laxa study coordinator – Second study coordinator coming soon! • Half student • Future genetic counselor Study coordinator roles • • • • • • Patient point of contact Answer questions Coordinate informed consent process Coordinate sample collection Coordinate Cutis Laxa Research Clinic Contact me any time! Genetic counselors help people understand and adapt to the genetic contributions of disase • Translate scientific and medical information • Give patients the power to make the decisions that are right for them • Talk with patients about emotional and social issues and connect them to resources Pittsburgh Pennylvania University of Pittsburgh Now that we are oriented… • • • • • • Overview of our research strategy Diagnosis of cutis laxa Genetics of cutis laxa Finding cutis laxa genes Finding out what cutis laxa genes do Fixing problems caused by changes in cutis laxa genes • Invitation to participate in our study Part One of Our Strategy: Cutis Laxa Clinic in Pittsburgh • Held twice per year, approximately 10 participants • Collect health information from different body systems – Skin, heart and blood vessels, lungs, skeleton, sometimes other systems • Collect genetic information • Match up health data with genetic data to understand different types of CL – goal: knowing what to expect Part Two of Our Strategy: In the Laboratory • Examine the genetic changes in study participants (blood/saliva test) • Find out how the genetic changes affect living cells – Grow cells from skin biopsies • test for levels of proteins and markers for cell activity – Artificially change similar genes in zebrafish and test Cutis laxa: diagnosis • Clinical examination and photographs • Skin biopsy • Few or fragmented elastic fibers in skin • Disorganization of elastic fibers • Mechanical measurements of the skin Mechanical measurements of the skin can identify cutis laxa Measurement of skin elasticity Research Question • What causes cutis laxa? – What are the genetic changes that cause cutis laxa? – How do these genetic changes cause cutis laxa? Genes are packaged into chromosomes Genes contain instructions for growth, development, and daily function Every gene has a job Many genes make proteins 23 pairs of chromosomes, one from each parent Autosomal Dominant Inheritance • 2 copies of each gene • 1 copy has a change that causes disease • ½ or 50% chance of inheriting disease with each pregnancy. • Equally affects males and females • Disease is often seen in multiple generations • Example: ELN-related cutis laxa (ADCL) Autosomal Recessive Inheritance • 2 copies of each gene • both copies have to have a change to cause disease • 1 copy of mutation = healthy carrier • ¼ or 25% chance of inheriting disease with each pregnancy. • Equally affects males and females • Usually seen in only 1 family member or sometimes siblings • Example: ATP6V0A2-related cutis laxa (ARCL2) Finding CL Genes: Look to see if CL is inherited with DNA markers on any chromosome 2 copies of marker 213 in children with cutis laxa Modified from Kornak et al. (2008) Nat Genet 40:32-34 Detecting missing or extra DNA • Gene chip: – Contains millions of small probes that cover all of the genes. Next generation sequencing Rapid discovery of new cutis laxa genes Research Question • Do changes in a gene cause cutis laxa? Compare skin cultured skin cells from affected and control individuals Genetic manipulation of mice Gene knockout Transgene Example: fibulin 4 (FBLN4) Autosomal recessive cutis laxa 1A Normally developing heart Twisted blood vessels and change in shape of heart Fibulin 4 knockout mouse embryos McLaughlin et al. (2006) Mol Cell Biol 26:1700-1709 Child with fibulin 4 mutation Hucthagowder et al. (2006) Am J Hum Genet 78:1075-1080 Genetic manipulation of zebrafish Mutant fish Transgene Gene knockdown in zebrafish using morpholino DNA protein Morpholino+ DNAno protein Research Question • How do changes in a gene cause cutis laxa? Gene network Studying gene interaction with “rescue” experiments: FBLN4 interacts with TGFBeta Typical fish embryo No FBLN4too much TGFBeta, problems with vessels and development No FBLN4 AND no TGFBeta 2 or 3 Fish develops normally Research Question • Can we do anything to treat cutis laxa? High throughput drug screening Drug treatment of cutis laxa gene deficiency What can you do? • Advocate for increase in scientific funding: • Support Charities: – March of Dimes – Cutis Laxa Internationale • Set up a US cutis laxa patient support group • Participate in research to help the next generation of people with cutis laxa DermaLab Skin Elasticity Testing • 15h 30 until end of day • Clinical study onging: [email protected]