Progeria pathophysiology: Difference between revisions
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'''Classic Hutchinson-Gilford progeria syndrome''' | '''Classic Hutchinson-Gilford progeria syndrome''' | ||
* The location of the [[Hutchinson-Gilford progeria syndrome]] (HGPS) gene was in 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> | * The location of the [[Hutchinson-Gilford progeria syndrome]] (HGPS) gene was in 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> | ||
*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. | ||
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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:
LMNA Gene
Classic Hutchinson-Gilford progeria syndrome
- The location of the Hutchinson-Gilford progeria syndrome (HGPS) gene was in chromosome 1q.[2][3]
- A single nucleotide substitution in the lamin A/C gene LMNA(c.1824C>T [p.Gly608Gly]) results in classic HGPS.[4]
- 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 at located in exon 11, C1824T of the LMNA gene results in activation of a cryptic splice donor site.[5]
- 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 due to 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.
- 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.
- And it is also thought that in Hutchinson-Gilford progeria syndrome telomere length is decreased gradually.[6]
Associated Conditions
Conditions associated with [disease name] include:
- [Condition 1]
- [Condition 2]
- [Condition 3]
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
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.
- ↑ 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.
- ↑ Madej-Pilarczyk A (2006). "[Hutchinson-Gilford progeria in the light of contemporary genetics]". Med Wieku Rozwoj. 10 (1 Pt 2): 355–62. PMID 17028399.
- ↑ 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.