Download Dr Michelle Murrow - cutis laxa internationale

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
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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…
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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+ DNAno 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 FBLN4too 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]