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XXXXXXXXXXXXXXXXXXXXXXXXXXXX PCB 3063, University of Florida, Gainesville, FL INTRODUCTION Hutchinson-Gilford Progeria Syndrome, an egregious laminopathy, develops in 1 in 4 million infants between ages 12 and 24 months. A single de novo autosomal dominant mutation in the LMNA gene can lead to pleiotropic defects in array of 1C different tissues, all stemming from nuclearmembrane buckling in somatic cells. Affected children suffer accelerated aging, cardiovascular defects, atherosclerosis, sclerotic skin, joint contractures, osteodysplasia, osteolysis, pathologic fractures, alopecia, growth retardation, Figure 1. Phenotypic effects of micrognathia, and a dearth of subcutaneous fat. HGPS 12 A. Picture of HGPS child manifesting Patients are not cognitively impaired and remain classic signs of an undersize jaw, mentally youthful as their bodies age. They most alopecia, lack of subcutaneous fat, often die from myocardial infarction or stroke and accelerated age. around thirteen years. B. Picture of normal nuclear lamina. 1A 1B C. Picture of “progerin-laden” nucleus with characteristic abnormal morphology. LMNA GENE GENE THERAPY MODES OF INHERITANCE Classical HGPS is primarily inherited in a de novo dominant autosomal manner with a G608G mutation; despite this, affected individuals usually die before reaching reproductive age. The de novo nature of this mutation is unsurprising given that the cysteine of the CpG dinucleotide is easily methylated and deaminated to produce TpG.4 Atypical HGPS was observed in a study performed by Plasilova et al.11 on a consanguineous Indian family that supported a recessive mode of inheritance. The heterozygous offspring exhibited the affected phenotype (Figure 4).The investigators used genome wide linkage analysis to restrict the gene locus to 1p13.3–1q23.3, and additional microsatellite markers for further specificity. LMNA mutation analysis was used to confirm a G to C transversion that resulted in a missense mutation; in this K542N, a charged amino acid, lysine, was replaced by uncharged asparagine within the DNA binding domain of the protein (Figure 5). Figure 4. Pedigree of four generations of an Indian family.11 Illustrates recessive inheritance. Consanguineous parents, I-1 and I-2, did not exhibit the disorder, and generated 5 heterozygous affected and 2 healthy offspring. The mapping of the LMNA gene, (Figure 2) was done by fluorescence in situ hybridization with a DAPI counter-stain. Thus, specific assignment was made based upon location or distance from DAPI bands and G-bands.14 MUTATIONS 1 •Despite the synonymous nature of this substitution, the mutation results in an unstable form of lamin A which generates a cryptic splice site that translates to an in-frame deletion of 150 nucleotides or 50 amino acids. •The LMNA gene actually codes for both lamin A and lamin C, but the mutation only affects the structure of lamin A because exon 11 of LMNA is not present in lamin C mRNA.2 Eriksson et al.4 was able to isolate the c.1824C>T mutation. Samples from 23 people diagnosed with classical HGPS underwent PCR amplification followed by direct sequencing for all of the exons of the LMNA gene. The resulting sequences revealed that a significant 18 people out of 23 people were found to be heterozygous for the c.1824C>T mutation. Figure 6. Contrasting posttranscriptional processing. The mutant pre-lamin A has a 50AA deletion and subsequently lacks the final cleavage step that is characteristic to normal mature lamin A production prior to incorporation into the nuclear lamina. http://www.ncbi.nlm.nih.gov/pmc/articl es/PMC2846822/ • • II 1 2 3 4 5 6 7 The most promising treatment aims to reverse the HGPS-cell phenotype via farnesyl transferase inhibitors (FTIs) FTIs bind to the CSIM sequence of pre-lamin A, blocking farnesyl transferase’s target and preventing farnesyl addition. Lacking the bulky substituent, progerin remains free from the INM. FTIs are inevitably toxic as many proteins require farnesylation to maintain proper functioning. Thus, FTIs are capable of disrupting normal cellular processes. CONCLUSION Figure 5 . Significance of K542N position. K542N mutation (yellow) results in an AA substitution of an uncharged residue in the place of a charged residue within the DNA binding domain, which is largely positively charged (blue). http://www.ncbi.nlm.nih.gov/pmc/a rticles/PMC2846822/ •Classical HPGS is most commonly caused by a c.1824C>T mutation. This C>T transition results in a silent Gly1824Gly mutation within the pre-lamin polypeptide. • • 2 The LMNA gene produces a polypeptide that requires post-translational processing to produce the mature lamin A protein, which functions as a nuclear protein scaffold significant to the integrity of the nuclear structure. In a study conducted by De SandreGiovannoli et al.2 on classical HGPS, a reverse transcriptase PCR isolated a normal transcript and a truncated mRNA transcript from lymphocytes derived from an affected child. The truncated transcript translated to a mutated form of pre-lamin A with an internal deletion of 50 amino acids, including the Zmpste24 cleavage site, due to activation of a cryptic splicing site. Thus, as seen in (Figure 6), the final cleavage of the 18 codons at the C terminus of the pre-lamin polypeptide cannot occur. Instead the resultant protein, progerin remains farnesylated (with a hydrocarbon at CAAX motif) and accumulates in the nuclear periphery.4 Progerin is then able intercalate into the nuclear membrane and dimerize with normal lamin A to form a protein complex that disrupts the intended protein scaffolding function; this results in the abnormal nuclear morphology characteristic of HGPS.1 Figure 3 . Table of HPGS mutations. c.1824C>T represents the most common classical mutation for HGPS. Atypical mutations are significantly more rare, but,are also presented. They can result in amino acid substitutions as well as alternative splice cites. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735 754/pdf/v041p00e67.pdf Because HGPS’s effect is not limited to specific tissue, but is instead universal to somatic cells, there is no way to selectively repair the deleterious mutations throughout the body. I PROTEIN Figure 2. LMNA gene position. mapped the LMNA gene to 1q21.2–q21.3, with emphasis on 1q21.3 as indicated by the black triangle. http://www.genecards.org/cgi-bin/carddisp.pl?gene=LMNA Figure 7. Immunofluorescence staining of fibroblasts.1 The three pictures depict a normal skin cell (far left), an HGPS skin cell (middle), and an FTI-treated HGPS skin cell (far right). Notice the near-restoration of the FTI-treated nuclear lamina’s spherical shape from the collapsed “progerin-laden” HGPS cell. Although rare, HGPS remains a great concern for its array of debilitating effects. Even more frustrating perhaps is its resistance to therapies. Despite knowing its exact location, 1q21.2, its somatic virulence eludes direct combat, relegating most medical interventions to high-calorie diets, careful playing with other children, and persistence. The most promising treatment, FTIs, offer the hope of rescuing the nuclear lamina from distortion in affected cells, but, again, at the risk of compromising other, healthy protein and cellular processes in the body. Nevertheless, HGPS offers intriguing insight into the massive epigenetic consequences of a single transition, swapping a cysteine for a thymine. REFERENCES 1. Capell, B.C., Erdos, M.R., Madigan, J.P., Fiordalisi, J.J., Varga, R., Conneely, K.N., Gordons, L.B., Der, C.J., Cox, A.D., Collins, F.S. (2005). Proc. Natl. Acad. Sci. USA. 102, 12879-12884. 2. Csoka, A.B., Cao, H., Sammak, P.J., Caonstantinescu, D., Schatten, G.P., Hegele, R.A. (2004). Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J. Med. Genet. 41, 304308. 3. De Sandre-Giovannoli, A., Bernard, R., Cau, P., Navarro, C., Amiel, J., Boccaccio, S.L., Stewart, C., Munnich, A., Le Merrer, M., Lévy, N. (2003). Lamin A Truncation in Hutchinson-Gilford Progeria. Science. 300, 2055. 4. Eriksson, M., Brown, W.T., Gordon, L.B., Glynns, M.W., Singer, J., Scott, L., Erdos, M.R., Robbins, C.M., Moses, T.Y., Berglund, P., et al., (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 423, 293-298. 5. Garg, A., Subramanyam, L., Agarwal, A.K., Simha, V., Levine, B., D’ Apice, M.R., Novelli, G., Crow, Y. (2009). Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations. J. Clin. Endocrinol. Metlab. 94, 4971-4983. 6. Gordon, L.B. (2011). Hutchinson-Gilford Progeria Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1121/#hgps.Management 7. Gordon, L.B., McCarten, K.M., Giobboe-Hurder, A., Machan, J.T., Campbell, S.E., Berns, S.D., Kieran, M.W. (2007). Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on Growth and Development. Pediatrics. 120, 824-833. 8. Glynn, M.W., Glover, T.W. (2005). Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Human Molecular Genetics. 14, 2959-2969. 9. Marji, J., O’Donoghue, S.I., McClintock, D., Satagopasm, V.P., Schneider, R., Ratner, D., Womran, H.J., Gordon, L.B., Djabali, K. Defective Lamin A-Rb Signling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition. PLoS Biol. 5, 1-14 10. McKusick, V.A. (2010). Hutchinson-Gilford Progeria Syndrome; HGPS. http://www.ncbi.nlm.nih.gov/omim/176670#BiochemicalFeatures-176670. 11. Plasilova, M., Chattopadhyay, C., Pal, P., Schaub, N.A., Buechner, S.A., Mueller, H., Miny, P., Ghosh, A., Heinimann, K. (2004). Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. 41, 609-614. 12. Raska, I. (2010). Importance of molecular cell biology investigations in human medicine in the story of the Hutchinson-Gilford progeria syndrome. Interdisc Toxicol. 3, 89-93. Scaffidi, P., Gordon, L., Misteli, T. (2005). The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. PLoS Biol. 3, 1855-1859. 13. Wydner, K.L., McNeil, J.A., Lin, F., Worman, H.J., Lawrence, J.B. (1996). Chromosomal Assignment of Human Nuclear Envelope Protein Genes LMNA, LMNB1, and LBR by FluorescenceinsityHybridization. Genomics. 32, 474-478. 14. Yang, S.H., Chang, A.Y., Ren, S., Wang, Y., Andres, D.A., Spielmann, H.P., Fong, L.G., Young, S.G. (2011). Absence of progeria-like disease phenotypes in knock-in mice expressing a nonfanesylated version of progerin. Human Molecular Genetics. 20, 436-444. lts in an unstable form of Lamin A which generates a cryptic site within the precursor mRNA for lamin A. The LMNA gene codes for both lamin A and lamin C, but the mutation only affects the structure of lamin A because exon 11 of LMNA is not present in lamin C mRNA m (Csoka, J Me e through a mutation on chromosome 1q at position 1822 of a Guanine to Adenine, a mutation on chromosome 1q at position 1921 of a Guanine to Adenine, a mild mutation: 35 amino acid deletion, a mutation at E145K, and a joint mutation of R471C and R527C (Csoka, J Med Genet 2 and severe disease phenotypes in affected patients. Retention of farnesyl group causes progerin to become permanently anchored in the nuclear membrane and unable to be released. The central rod domain of progerin then allows dimerization with mature nonfarnesylated LA and asse The LMNA gene was mapped to 1q21.2–q21.3, with positional emphasis on 1q21.3, as determined by fluorescence in situ hybridization with a DAPI counter-stain. I 1 2 II 1 2 3 4 5 6 7 I 1 2 II 1 2 3 4 5 6 7 1. De Sandre-Giovannoli, A., Bernard, R., Cau, P., Navarro, C., Amiel, J., Boccaccio, S.L., Stewart, C., Munnich, A., Le Merrer, M., Lévy, N. (2003). Lamin A Truncation in Hutchinson-Gilford Progeria. Science. 300, 2055. 2. Domingo, D.L., Trujillo, M.I., Council, S.E., Merideth, M.A., Gordon, L.B., Wu, T., Introne, W.J., Gahl, W.A., Hart, T.C. (2009). Hutchinson-Gilford progeria syndrome: Oral and craniofacial phenotypes. Oral Dis. 15, 187-195. 3. Eriksson, M., Brown, W.T., Gordon, L.B., Glynns, M.W., Singer, J., Scott, L., Erdos, M.R., Robbins, C.M., Moses, T.Y., Berglund, P., et al., (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 423, 293-298. 4. Garg, A., Subramanyam, L., Agarwal, A.K., Simha, V., Levine, B., D’ Apice, M.R., Novelli, G., Crow, Y. (2009). Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations. J. Clin. Endocrinol. Metlab. 94, 4971-4983. 5. Gordon, L.B. (2011). Hutchinson-Gilford Progeria Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1121/#hgps.Management 6. Gordon, L.B., McCarten, K.M., Giobboe-Hurder, A., Machan, J.T., Campbell, S.E., Berns, S.D., Kieran, M.W. (2007). Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on Growth and Development. Pediatrics. 120, 824833. 7. Glynn, M.W., Glover, T.W. (2005). Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Human Molecular Genetics. 14, 2959-2969. 8.Marji, J., O’Donoghue, S.I., McClintock, D., Satagopasm, V.P., Schneider, R., Ratner, D., Womran, H.J., Gordon, L.B., Djabali, K. Defective Lamin A-Rb Signling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition. PLoS Biol. 5, 1-14 9. McKusick, V.A. (2010). Hutchinson-Gilford Progeria Syndrome; HGPS. http://www.ncbi.nlm.nih.gov/omim/176670#BiochemicalFeatures-176670. 10. Plasilova, M., Chattopadhyay, C., Pal, P., Schaub, N.A., Buechner, S.A., Mueller, H., Miny, P., Ghosh, A., Heinimann, K. (2004). Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. 41, 609-614. 11. Raska, I. (2010). Importance of molecular cell biology investigations in human medicine in the story of the Hutchinson-Gilford progeria syndrome. The majority of patients with HGPS have de novo heterozygous dominant mutations in the LMNA gene. Presumably, patients with the disorder do not survive long enough to reproduce (Eriksson et al., 2003; Cao and Hegele, 2003).