LMNA and its role in HutchinsonGilford 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 -IHAYRKLLEIF protein
• Sequences returned expected
motifs and accompanying
domains
• Main components of nuclear
lamins
• Tail domain is contains NLS
Images taken from: Pfam
IF tail
domain
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
Biological Process
Cellular Component
• Protein binding
• Muscle development
• Lamin filament
• Structural molecular
activity
• More associated with
Charcot-Emery
disease
• Nuclear envelope
• Perinuclear region of
cytoplasm
Protein interactions
Mouse
Human
• ZMPSTE24 could be a focus
• Mutations of this protein cause similar phenotypes when
compared to HGPS
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.