LMNA and its role in Hutchinson-Gilford Progeria Syndrome

(HGPS)

Peter St. Andre

Outline

• Background– Overview of HGPS– Discovery and role of LMNA in HGPS

• Gene and protein data– Homology, phylogeny,domains, ontology, and

interactions

• Further directions– New angles at research– Current drug trials

Background on disease

• Characterized by premature accelerated aging beginning between 6-12 months of age

• There are around 100 living patients worldwide at a given time

• Often fatal by the age of 13 with no known cure

maldova.org

Quick facts about HGPS

• Symptoms include: hair loss, scleroderma, severe arthritis, etc.

• Differs from other known progeroid diseases

• Fastest time from discovery to drug trials

Susana Lopez, 21, is the oldest known sufferer of HGPS health.tbo.com

Cause of HGPS• Able to discover cause of disease incredibly quickly

• de novo mutations occur in exon 11 of LMNA gene

• >70% are 1824C>T (G608G) mutations, with ~10% 1821G>A (V607V)

• LMNA produces lamin A/C proteins and through alternate splicing three isoforms can be created

• Mutation does not allow for cleavage to produce a mature functional lamin A

Mutation behind HGPS

Protein motifs and domains

• 9 aa seq. recognized as IF domain -IHAYRKLLE-

• Sequences returned expected motifs and accompanying domains

• Main components of nuclear lamins

• Tail domain is contains NLS

IF protein

IF tail domain

Images taken from: Pfam

Homology

•Lmn-1 is homolog in C. elegans

•Only lamin in C. elegans, predecessor of all lamins?

Homo sapiens 664 aa

C. elegans 566 aa

Phylogeny

•Differences between branches is very small

•Zebrafish still has 63% identity

•Run through several programs all returned exact phylogeny

Gene ontology

Molecular Function

• Protein binding

• Structural molecular activity

Biological Process

• Muscle development

• More associated with Charcot-Emery disease

Cellular Component

• Lamin filament

• Nuclear envelope

• Perinuclear region of cytoplasm

Protein interactions

• ZMPSTE24 could be a focus

• Mutations of this protein cause similar phenotypes when compared to HGPS

Mouse Human

FTI clinical trials

• Drug trial began in 2007 and are expected to finish later this year

• While there is evidence in mice of rescuing phenotypes, in humans FTIs seem unlikely to solve anything

• Patients symptoms become too severe too quickly

• Still have a dysfunctional lamin A protein

Further research

• FTIs offer promise and a start

• Run 2D-gel analyses as lamins are characterized by pI

• Focus on the post-translational modifications

• Key would be to induce cleavage of farnesylated end therefore producing mature lamin A

Special thanks to:

Dr. Ahna Skop

Dr. Robert Goldman

Peers

References

Eriksson, M., Brown, W. T., Gordon, L. B., Glynn, M. W., Singer, J., Scott, L., Erdos, M. R., Robbins, C. M., Moses, T. Y., Berglund, P., Dutra, A., Pak, E., Durkin, S., Csoka, A. B., Boehnke, M., Glover, T. W., & Collins, F. S. (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, 423, 293-298. doi: 10.1038/nature01629

Meta, M., Yang, S. H., Bergo, M. O., Fong, L. G., & Young, S. G. (2006). Protein farnesyltransferase inhibitors and progeria. Trends in Molecular Medicine, 12(10), 480-487. doi: 10.1016/j.molmed.2006.08.006

Sagelius, H., Rosengardten, Y., Hanif, M., Erdos, M., Rozell, B., Collins, F., & Eriksson, M. (2008). Targeted transgenic expression of the mutation causing Hutchinson-Gilford progeria syndrome leads to proliferative and degenerative epidermal disease. Journal of Cell Science, 121, 969-978. doi: 10.1242/jcs.022913

Ruchaud, S., Korfall, N., Villa, P., Kottke, T., Dingwall, C., Kaufmann, F., Earnshaw,, W. (2002). Caspase-6 gene disruption reveals a requirement for lamin A in apoptotic chromatin decondensation. The EMPBO Journal (21). Retrieved from: The EMBO Journal.

Moulson CL, Fong LG, Gardner JM, Farber EA, Go G, Passariello A, Grange DK, Young SG, Miner GH. (2007). Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Human Mutations 28(9). PMID: 17469202.