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We hoped you learned that Ellis van Creveld is a very interesting genetic disorder showing you how the founder effect works in a human population as well as showing the development of the affected individuals. People with this disorder show abnormalities in all regions of the body which means that this gene plays a vital role in the major development of our bodies. Since the exact location of the EVC and EVC2 protein are not well known it is important for research to continue. The implications of this gene could help us get a better understanding of how humans develop in the embryo as well as how any abnormal growth occurs.

Nina, Ninosca, Morgan, and Surui thank you for visiting!

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EVC Around the World

-Ellis van Creveld syndrome affects many different parts of the body including tissues, organs, and skeletal structure

--The three main features after birth include

-extra fingers in hands or feet (polydactyly)

-short stature and shorter arms, legs, or ribcage

-Dysplasia in teeth, hair, or nails

-The table above shows the expression of these genes in different organs of the body

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EVC and EVC2 Expression

There are actually two genes that are responsible for Ellis van Creveld syndrome, but both do not count for all the reported casesThe genes, EVC and EVC2 are both located on the 4th chromosome in the 16.1 and 16.2 position (as indicated by the yellow arrow)

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EVC the Introduction

Overview Paper: http://www.biomedcentral.com/content/pdf/1750-1172-2-27.pdf&embedded=true

-The genes involved in Ellis van Creveld syndrome do not account for all the differences in this genetic disorder meaning that there can be more at work to create the disorder

-Since these genes tend to affect many of the major organs in the body it is important to understand the pathway of this disorder

-Ongoing research also shows that a disrupted hedgehog pathway (a mutation caused by these genes) can also cause cancer, further study of this gene can lead to a better understanding and treatment options for cancer

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Why is it Important?

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How the Pathway Works

-When the Hedgehog ligand attaches to the Patched protein a cascade of signals are sent in the cell that ultimately lead to the activation of Ci, a factor that helps for the hedgehog target to be transcribed for replication

A more molecular view is available here:http://www.dnatube.com/video/5854/Video-of-Hedgehog-signalling-pathway

-EVC and EVC2 are novel proteins important in the creation of purmorphamine (an agonist of Smoothened, the regulator of the Ihh pathway).

-This pathway is important in cell differentiation and organ development in embryos

-Both EVC and EVC2 are cilia transmembrane proteins

-The underproduction caused by a disruption in the pathway can lead to malformed organs or skeletal structures while the stimulation of the pathway can lead to tumor growth

-This also plays a role in the regulation of stem cells in the adult human body

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Hedgehog Pathway

Paper :http://www.biomedcentral.com/1741-7007/9/14/

More on Embryonic Development: http://www.biooncology.com/research-education/hedgehog/overview/embryonic/index.html

-There are three different ligands for the Hedgehog pathway available in a human and each have their own specific reaction when they reach the end of the signaling pathway

-Sonic Hedgehog (Shh): shown to alter limb and heart formation

-Indian Hedgehog (Ihh): shown to alter bone development

-Desert Hedgehog (Dhh): shown to alter ganglia and intestines

-EVC and EVC2 do not code for the ligands only for a regulatory component in the pathway that allows each of these ligands to be processed for their ultimate function

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Hedgehog Ligands

This picture shows the hedgehog gene in drosophila development (the top is the normal type)

Detailed Paper on Pathway: http://www.abcam.com/index.html?pageconfig=resource&rid=10858&pid=10039

-EVC codes for a 992 amino acid protein which contains a leucine zipper. Mutation leads to the creation of proline amino acid that leucine, which is important

-A leucine zipper is a transcription factor that regulates DNA transcription

-EVC plays a role in the hedgehog pathway regulation one of which is hypothesized to be this DNA leucine zipper formation

-With an improper attachment to the DNA, the targeted cells DNA is not duplicated for the end products of the targeted cell development

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The Leucine Zipper

Leucine Zipper and DNA implications: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC450290/pdf/emboj00004-0235.pdf

Sonic Hedgehog, Indian Hedgehog, and Desert Hedgehog are all different hedgehog pathway ligands found in humans. Arent hedgehogs already prickly? We dont need anymore prickly things.

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You sure are smart

-EVC2 codes for a protein called Limbin

-This limbin molecule is shown to have a role in regulation of the hedgehog pathway although it is not entirely understood

-It is believed that this protein acts as a signal carrier because it is found in both the nucleus of the cell and the basal portion of the cilia

-EVC2 can also affect signaling because it facilitates the attachment of EVC to the cilia

-Any disruption a the signal pathway can lead to defects that depend on the ligands

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Limbin

Paper on Cilia and Regulation:

http://www.biomedcentral.com/1741-7007/9/14

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Which one is NOT a Hedgehog Pathway Ligand?

Indian Hedgehog

Sonic Hedgehog

Prickly Hedgehog

Desert Hedgehog

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Name this structure

Leucine Zipper

Hedgehog Pathway

Hedgehog Ligand

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You mean to tell me you didnt look around enough?

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Which one of these is NOT an effect of EVC and EVC2?

Abnormal Skeletal Growth

Extra Fingers

Tall Stature

-This disorder has a 25% pattern of inheritance

-There are more than 2000 different mutations for both portions of the EVC gene each containing two different alleles

-This is a very novel disorder that seems to show about 150 cases a year, but many new cases have been reported even outside of the normal Amish communities where it is prevalent

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Variance of Ellis van Creveld

Some of the DNA sequencing

mutations of this disorder show that the bases highlighted are switched

rs735171
AAGAGGGCTCAGGTGT/CCCTCTCCTGCTCTCT

rs748233
CCCCACTCCCAGCCAC/TGCCCAGCTCAGGCCT

rs752061
TTGAGCCTTGCCCCAC/TCCCCACCCCAGGGTC

The following is a link to an interactive map for the distribution of Ellis van Creveld

http://www.zeemaps.com/pub?group=439061

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Distribution Map

Around the World Data

in general, population: --.07/100,000 live births
-5.2/100,000 live births in theUnited Arab Emirates
-500/100,000 live births in the Amish of Pennsylvania
-.5-2/100,000 live births in Sweden

parental consanguity in 30% of cases

-Found effect shows that a certain few leave the population to go colonize in the other

-With each new population the risk of recessive gene mutations increases

-Ellis van Creveld is an autosomal recessive gene and is prevalent in the Amish communities

-The Amish migrated in small colonies and show the same signs of the founder effect

-PBS knows the Amish: http://www.pbs.org/wgbh/evolution/library/06/3/l_063_03.html

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Founder Effect and Ellis van Creveld

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You sure are smart

That is the leucine zipper which is one of the products from the protein EVC codes for.

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You sure are smart

Extra fingers and abnormal skeletal structure are definitely products of this disorder however being tall is definitely not one of them. People with this disorder are categorized as having a small stature