Progeria pathophysiology: Difference between revisions
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==Genetics== | ==Genetics== | ||
Genes involved in the pathogenesis of [[Hutchinson-Gilford progeria syndrome]] (HGPS) include: | [[Gene|Genes]] involved in the [[pathogenesis]] of [[Hutchinson-Gilford progeria syndrome]] (HGPS) include:<ref name="pmid154791793">{{cite journal| author=Pollex RL, Hegele RA| title=Hutchinson-Gilford progeria syndrome. | journal=Clin Genet | year= 2004 | volume= 66 | issue= 5 | pages= 375-81 | pmid=15479179 | doi=10.1111/j.1399-0004.2004.00315.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15479179 }}</ref> | ||
'''''LMNA Gene''''' | '''''LMNA Gene''''' | ||
| Line 18: | Line 18: | ||
'''Classic Hutchinson-Gilford progeria syndrome''' | '''Classic Hutchinson-Gilford progeria syndrome''' | ||
* The location of the [[Hutchinson-Gilford progeria syndrome]] (HGPS) gene was | * The location of the [[Hutchinson-Gilford progeria syndrome]] (HGPS) [[gene]] was at [[chromosome]] 1q.<ref name="pmid12714972">{{cite journal| author=Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L et al.| title=Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. | journal=Nature | year= 2003 | volume= 423 | issue= 6937 | pages= 293-8 | pmid=12714972 | doi=10.1038/nature01629 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12714972 }}</ref><ref name="pmid19428457">{{cite journal| author=Decker ML, Chavez E, Vulto I, Lansdorp PM| title=Telomere length in Hutchinson-Gilford progeria syndrome. | journal=Mech Ageing Dev | year= 2009 | volume= 130 | issue= 6 | pages= 377-83 | pmid=19428457 | doi=10.1016/j.mad.2009.03.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19428457 }}</ref> | ||
*A single [[nucleotide]] [[substitution]] in the [[Lamin A|lamin]] A/C [[gene]] ''[[LMNA]](c.1824C>T [p.Gly608Gly])'' results in classic [[Progeria|HGPS]].<ref name="pmid154791792">{{cite journal| author=Pollex RL, Hegele RA| title=Hutchinson-Gilford progeria syndrome. | journal=Clin Genet | year= 2004 | volume= 66 | issue= 5 | pages= 375-81 | pmid=15479179 | doi=10.1111/j.1399-0004.2004.00315.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15479179 }}</ref> | *A single [[nucleotide]] [[substitution]] in the [[Lamin A|lamin]] A/C [[gene]] ''[[LMNA]](c.1824C>T [p.Gly608Gly])'' results in classic [[Progeria|HGPS]].<ref name="pmid154791792">{{cite journal| author=Pollex RL, Hegele RA| title=Hutchinson-Gilford progeria syndrome. | journal=Clin Genet | year= 2004 | volume= 66 | issue= 5 | pages= 375-81 | pmid=15479179 | doi=10.1111/j.1399-0004.2004.00315.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15479179 }}</ref><ref name="pmid12768443">{{cite journal| author=Cao H, Hegele RA| title=LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). | journal=J Hum Genet | year= 2003 | volume= 48 | issue= 5 | pages= 271-4 | pmid=12768443 | doi=10.1007/s10038-003-0025-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12768443 }}</ref><ref name="pmid17459035">{{cite journal| author=Mazereeuw-Hautier J, Wilson LC, Mohammed S, Smallwood D, Shackleton S, Atherton DJ et al.| title=Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature. | journal=Br J Dermatol | year= 2007 | volume= 156 | issue= 6 | pages= 1308-14 | pmid=17459035 | doi=10.1111/j.1365-2133.2007.07897.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17459035 }}</ref> | ||
*The [[mutation]] does not change the position of [[glycine]] at 608 in [[protein]] chain. | *The [[mutation]] does not change the position of [[glycine]] at 608 in [[protein]] chain. | ||
*''[[De novo]]'' [[dominant]] [[mutation]] in the ''[[LMNA]]'' [[gene]] causes classic [[Progeria|HGPS]]. | *''[[De novo]]'' [[dominant]] [[mutation]] in the ''[[LMNA]]'' [[gene]] causes classic [[Progeria|HGPS]]. | ||
* A single [[de novo]] [[dominant]] [[mutation]] at C to T pathogenic variant at | * A single [[de novo]] [[dominant]] [[mutation]] at C to T pathogenic variant which is located at [[exon]] 11, C1824T of the ''[[LMNA]]'' gene results in activation of a [[Cryptic splice site|cryptic]] [[Splice site|splice]] [[donor]] site.<ref name="pmid17028399">{{cite journal| author=Madej-Pilarczyk A| title=[Hutchinson-Gilford progeria in the light of contemporary genetics]. | journal=Med Wieku Rozwoj | year= 2006 | volume= 10 | issue= 1 Pt 2 | pages= 355-62 | pmid=17028399 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17028399 }}</ref> | ||
*Now at [[Cryptic splice site|cryptic]] [[Splice site|splice]] [[donor]] site there is formation of a messenger RNA with a 150-nucleotide internal deletion near the C-terminus of the chain. | *Now at [[Cryptic splice site|cryptic]] [[Splice site|splice]] [[donor]] site there is formation of a [[messenger RNA]] with a 150-[[nucleotide]] internal deletion near the [[C-terminus]] of the chain. | ||
*The resultant of the [[mutation]] leads to formation of short [[lamin A]] [[protein]] which is called [[progerin]]. | *The resultant of the [[mutation]] leads to formation of short [[lamin A]] [[protein]] which is called [[progerin]]. | ||
*Progerin has a 50-amino acid internal deletion due to de novo dominant mutation. | *[[Progerin]] has a 50-[[amino acid]] internal deletion along with CAAX box [[farnesylation]] site due to [[De novo mutation|de novo]] dominant [[mutation]]. | ||
*Now the progerin which has 50-amino acid misses cleave site due to internal deletion which results in continuous farnesylation which in turn results in progerin anchored to the nuclear envelope. | *Now the [[progerin]] which has 50-[[amino acid]] misses the cleave site, due to internal [[deletion]] which results in continuous [[farnesylation]] which in turn results in [[progerin]] anchored to the [[nuclear]] envelope.<ref name="pmid16126733">{{cite journal| author=Glynn MW, Glover TW| title=Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. | journal=Hum Mol Genet | year= 2005 | volume= 14 | issue= 20 | pages= 2959-69 | pmid=16126733 | doi=10.1093/hmg/ddi326 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16126733 }}</ref> | ||
*This continuous farnesylation thought be the cause of the disease and results in following changes: | *This continuous [[farnesylation]] thought be the cause of the [[disease]] and results in following changes: | ||
**Nuclear blebbing | **[[Nuclear]] [[blebbing]] | ||
**Disorganized heterochromatin | **Disorganized [[heterochromatin]] | ||
**Dysregulated gene transcription | **Dysregulated [[gene]] [[Transcription (genetics)|transcription]] | ||
*This whole unexpected sequences in the cell leads to genomic instability and may leads to premature aging and disease in [[Hutchinson-Gilford progeria syndrome]]. | *This whole unexpected sequences in the cell leads to [[Genomics|genomic]] instability and may leads to premature [[Ageing|aging]] and disease in [[Hutchinson-Gilford progeria syndrome]].<ref name="pmid15268757">{{cite journal| author=Csoka AB, English SB, Simkevich CP, Ginzinger DG, Butte AJ, Schatten GP et al.| title=Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. | journal=Aging Cell | year= 2004 | volume= 3 | issue= 4 | pages= 235-43 | pmid=15268757 | doi=10.1111/j.1474-9728.2004.00105.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15268757 }}</ref> | ||
*And it is also thought that in [[Hutchinson-Gilford progeria syndrome]] telomere length is decreased gradually.<ref name="pmid1438199">{{cite journal| author=Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB et al.| title=Telomere length predicts replicative capacity of human fibroblasts. | journal=Proc Natl Acad Sci U S A | year= 1992 | volume= 89 | issue= 21 | pages= 10114-8 | pmid=1438199 | doi=10.1073/pnas.89.21.10114 | pmc=50288 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1438199 }}</ref> | *And it is also thought that in [[Hutchinson-Gilford progeria syndrome]] [[telomere]] length is decreased gradually.<ref name="pmid1438199">{{cite journal| author=Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB et al.| title=Telomere length predicts replicative capacity of human fibroblasts. | journal=Proc Natl Acad Sci U S A | year= 1992 | volume= 89 | issue= 21 | pages= 10114-8 | pmid=1438199 | doi=10.1073/pnas.89.21.10114 | pmc=50288 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1438199 }}</ref> | ||
=== Atypical progeria syndromes === | |||
* | *The cause of atypical [[progeria]] [[Syndrome|syndromes]] is almost similar to Classic [[Hutchinson-Gilford progeria syndrome]] except the [[Mutation|mutations]] are mostly occurs in intron 11 of the [[LMNA]] [[gene]] where as in Classic [[Hutchinson-Gilford progeria syndrome|Hutchinson-Gilford progeria]] the [[mutations]] occurs in c.1824C>T [p.Gly608Gly].<ref name="pmid17469202">{{cite journal| author=Moulson CL, Fong LG, Gardner JM, Farber EA, Go G, Passariello A et al.| title=Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. | journal=Hum Mutat | year= 2007 | volume= 28 | issue= 9 | pages= 882-9 | pmid=17469202 | doi=10.1002/humu.20536 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17469202 }} </ref><ref name="pmid23969228">{{cite journal| author=Rivera-Torres J, Acín-Perez R, Cabezas-Sánchez P, Osorio FG, Gonzalez-Gómez C, Megias D et al.| title=Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture. | journal=J Proteomics | year= 2013 | volume= 91 | issue= | pages= 466-77 | pmid=23969228 | doi=10.1016/j.jprot.2013.08.008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23969228 }} </ref> | ||
== | |||
==References== | ==References== | ||
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{{WH}} | {{WH}} | ||
{{WS}} | {{WS}} | ||
[[Category: | [[Category:Rare disease]] | ||
Latest revision as of 15:11, 16 July 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]
Overview
It is thought that Hutchinson-Gilford progeria is the result due to mutation in LMNA gene.
Pathophysiology
Pathogenesis
- It is understood that Hutchinson-Gilford progeria is the result due to mutation in LMNA gene.[1]
Genetics
Genes involved in the pathogenesis of Hutchinson-Gilford progeria syndrome (HGPS) include:[2]
LMNA Gene
Classic Hutchinson-Gilford progeria syndrome
- The location of the Hutchinson-Gilford progeria syndrome (HGPS) gene was at chromosome 1q.[3][4]
- A single nucleotide substitution in the lamin A/C gene LMNA(c.1824C>T [p.Gly608Gly]) results in classic HGPS.[5][6][7]
- The mutation does not change the position of glycine at 608 in protein chain.
- De novo dominant mutation in the LMNA gene causes classic HGPS.
- A single de novo dominant mutation at C to T pathogenic variant which is located at exon 11, C1824T of the LMNA gene results in activation of a cryptic splice donor site.[8]
- Now at cryptic splice donor site there is formation of a messenger RNA with a 150-nucleotide internal deletion near the C-terminus of the chain.
- The resultant of the mutation leads to formation of short lamin A protein which is called progerin.
- Progerin has a 50-amino acid internal deletion along with CAAX box farnesylation site due to de novo dominant mutation.
- Now the progerin which has 50-amino acid misses the cleave site, due to internal deletion which results in continuous farnesylation which in turn results in progerin anchored to the nuclear envelope.[9]
- This continuous farnesylation thought be the cause of the disease and results in following changes:
- Nuclear blebbing
- Disorganized heterochromatin
- Dysregulated gene transcription
- This whole unexpected sequences in the cell leads to genomic instability and may leads to premature aging and disease in Hutchinson-Gilford progeria syndrome.[10]
- And it is also thought that in Hutchinson-Gilford progeria syndrome telomere length is decreased gradually.[11]
Atypical progeria syndromes
- The cause of atypical progeria syndromes is almost similar to Classic Hutchinson-Gilford progeria syndrome except the mutations are mostly occurs in intron 11 of the LMNA gene where as in Classic Hutchinson-Gilford progeria the mutations occurs in c.1824C>T [p.Gly608Gly].[12][13]
References
- ↑ Pollex RL, Hegele RA (2004). "Hutchinson-Gilford progeria syndrome". Clin Genet. 66 (5): 375–81. doi:10.1111/j.1399-0004.2004.00315.x. PMID 15479179.
- ↑ Pollex RL, Hegele RA (2004). "Hutchinson-Gilford progeria syndrome". Clin Genet. 66 (5): 375–81. doi:10.1111/j.1399-0004.2004.00315.x. PMID 15479179.
- ↑ Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L; et al. (2003). "Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome". Nature. 423 (6937): 293–8. doi:10.1038/nature01629. PMID 12714972.
- ↑ Decker ML, Chavez E, Vulto I, Lansdorp PM (2009). "Telomere length in Hutchinson-Gilford progeria syndrome". Mech Ageing Dev. 130 (6): 377–83. doi:10.1016/j.mad.2009.03.001. PMID 19428457.
- ↑ Pollex RL, Hegele RA (2004). "Hutchinson-Gilford progeria syndrome". Clin Genet. 66 (5): 375–81. doi:10.1111/j.1399-0004.2004.00315.x. PMID 15479179.
- ↑ Cao H, Hegele RA (2003). "LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090)". J Hum Genet. 48 (5): 271–4. doi:10.1007/s10038-003-0025-3. PMID 12768443.
- ↑ Mazereeuw-Hautier J, Wilson LC, Mohammed S, Smallwood D, Shackleton S, Atherton DJ; et al. (2007). "Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature". Br J Dermatol. 156 (6): 1308–14. doi:10.1111/j.1365-2133.2007.07897.x. PMID 17459035.
- ↑ Madej-Pilarczyk A (2006). "[Hutchinson-Gilford progeria in the light of contemporary genetics]". Med Wieku Rozwoj. 10 (1 Pt 2): 355–62. PMID 17028399.
- ↑ Glynn MW, Glover TW (2005). "Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition". Hum Mol Genet. 14 (20): 2959–69. doi:10.1093/hmg/ddi326. PMID 16126733.
- ↑ Csoka AB, English SB, Simkevich CP, Ginzinger DG, Butte AJ, Schatten GP; et al. (2004). "Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis". Aging Cell. 3 (4): 235–43. doi:10.1111/j.1474-9728.2004.00105.x. PMID 15268757.
- ↑ Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB; et al. (1992). "Telomere length predicts replicative capacity of human fibroblasts". Proc Natl Acad Sci U S A. 89 (21): 10114–8. doi:10.1073/pnas.89.21.10114. PMC 50288. PMID 1438199.
- ↑ Moulson CL, Fong LG, Gardner JM, Farber EA, Go G, Passariello A; et al. (2007). "Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes". Hum Mutat. 28 (9): 882–9. doi:10.1002/humu.20536. PMID 17469202.
- ↑ Rivera-Torres J, Acín-Perez R, Cabezas-Sánchez P, Osorio FG, Gonzalez-Gómez C, Megias D; et al. (2013). "Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture". J Proteomics. 91: 466–77. doi:10.1016/j.jprot.2013.08.008. PMID 23969228.