Progeria pathophysiology: Difference between revisions

Jump to navigation Jump to search
 
Line 12: Line 12:


==Genetics==
==Genetics==
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>
[[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 23: Line 23:
*''[[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 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>
* 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 along with CAAX box [[farnesylation]] site due to [[De novo mutation|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 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>
*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]].<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>
*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
 
=== 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>
*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>



Latest revision as of 15:11, 16 July 2019

Progeria Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Progeria from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Interventions

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Progeria pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Progeria pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Progeria pathophysiology

CDC on Progeria pathophysiology

Progeria pathophysiology in the news

Blogs on Progeria pathophysiology

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for Progeria pathophysiology

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

Genetics

Genes involved in the pathogenesis of Hutchinson-Gilford progeria syndrome (HGPS) include:[2]

LMNA Gene

Classic Hutchinson-Gilford progeria syndrome

Atypical progeria syndromes

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Madej-Pilarczyk A (2006). "[Hutchinson-Gilford progeria in the light of contemporary genetics]". Med Wieku Rozwoj. 10 (1 Pt 2): 355–62. PMID 17028399.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.

Template:WH Template:WS