Leopard syndrome pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Leopard syndrome has been associated with mutations | Leopard syndrome is most commonly caused by [[missense mutation]]s in the [[PTPN11]] gene. It has also been associated with other gene mutations such as [[c-Raf|RAF1]] and [[BRAF]]. | ||
Molecular studies have shown that Leopard syndrome is caused by different missense mutations in [[PTPN11]].<ref name="pmid16523510">{{cite journal| author=Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R et al.| title=LEOPARD syndrome: clinical diagnosis in the first year of life. | journal=Am J Med Genet A | year= 2006 | volume= 140 | issue= 7 | pages= 740-6 | pmid=16523510 | doi=10.1002/ajmg.a.31156 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16523510 }} </ref> Mutations cause a loss of [[catalytic activity]] of the SHP2 protein, which is a previously unrecognized behavior for this class of mutations.<ref name="pmid16358218">{{cite journal| author=Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V et al.| title=Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | journal=Am J Hum Genet | year= 2006 | volume= 78 | issue= 2 | pages= 279-90 | pmid=16358218 | doi=10.1086/499925 | pmc=PMC1380235 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16358218 }} </ref> This interferes with growth factor and related signalling. | ==Pathophysiology== | ||
===Genetics=== | |||
Molecular studies have shown that Leopard syndrome is caused by different missense mutations in [[PTPN11]].<ref name="pmid16523510">{{cite journal| author=Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R et al.| title=LEOPARD syndrome: clinical diagnosis in the first year of life. | journal=Am J Med Genet A|year= 2006 | volume= 140 | issue= 7 | pages= 740-6 | pmid=16523510 | doi=10.1002/ajmg.a.31156 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16523510 }} </ref> Mutations cause a loss of [[catalytic activity]] of the SHP2 protein, which is a previously unrecognized behavior for this class of mutations.<ref name="pmid16358218">{{cite journal| author=Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V et al.| title=Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | journal=Am J Hum Genet | year= 2006 | volume= 78 | issue= 2 | pages= 279-90 | pmid=16358218 | doi=10.1086/499925 | pmc=PMC1380235 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16358218 }} </ref> This interferes with growth factor and related signalling. | |||
In the two predominant mutations of Leopard syndrome, the mutations cause a loss of [[catalytic activity]] of the SHP2 protein(the gene product of the ''[[PTPN11]]'' gene located at chromosome 12q22-qter), which is a previously unrecognized behavior for this class of mutations.<ref>{{cite journal |author=Tartaglia M, Martinelli S, Stella L, ''et al'' |title=Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease |journal=Am. J. Hum. Genet. |volume=78 |issue=2|pages=279–90 |year=2006 |pmid=16358218 |doi=10.1086/499925}}</ref> This interferes with growth factor and related signalling. While further research confirms this mechanism,<ref>{{cite journal |author=Hanna N, Montagner A, Lee WH, ''et al'' |title=Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1 |journal=FEBS Lett. |volume=580 |issue=10 |pages=2477–82 |year=2006 |pmid=16638574 |doi=10.1016/j.febslet.2006.03.088}}</ref><ref>{{cite journal|author=Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG |title=PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects|journal=J. Biol. Chem. |volume=281 |issue=10 |pages=6785–92 |year=2006 |pmid=16377799|doi=10.1074/jbc.M513068200|url=http://www.jbc.org/cgi/content/full/281/10/6785}}</ref> additional research is needed to determine how this relates to all of the observed effects of Leopard syndrome. | |||
In the two predominant mutations of Leopard syndrome, the mutations cause a loss of [[catalytic activity]] of the SHP2 protein(the gene product of the ''[[PTPN11]]'' gene located at chromosome 12q22-qter), which is a previously unrecognized behavior for this class of mutations.<ref>{{cite journal |author=Tartaglia M, Martinelli S, Stella L, ''et al'' |title=Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease |journal=Am. J. Hum. Genet. |volume=78 |issue=2 |pages=279–90 |year=2006 |pmid=16358218 |doi=10.1086/499925}}</ref> This interferes with growth factor and related signalling. While further research confirms this mechanism,<ref>{{cite journal |author=Hanna N, Montagner A, Lee WH, ''et al'' |title=Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1 |journal=FEBS Lett. |volume=580 |issue=10 |pages=2477–82 |year=2006 |pmid=16638574 |doi=10.1016/j.febslet.2006.03.088}}</ref><ref>{{cite journal |author=Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG |title=PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects |journal=J. Biol. Chem. |volume=281 |issue=10 |pages=6785–92 |year=2006 |pmid=16377799 |doi=10.1074/jbc.M513068200|url=http://www.jbc.org/cgi/content/full/281/10/6785}}</ref> additional research is needed to determine how this relates to all of the observed effects of Leopard syndrome. | |||
=== | ===Associated Conditions=== | ||
Diagnosis of Leopard syndrome is sometimes difficult because of the overlap with [[Noonan syndrome]] and [[neurofibromatosis 1]]. In these patients, the presence of the disease can be confirmed with a mutation-based diagnosis, laboratory studies should include molecular analysis of the [[PTPN11]] and [[c-Raf|RAF1]] genes. In a study of 10 infants with clinical indications of Leopard syndrome prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient, with the suspected mutation was subsequently found to have [[Neurofibromatosis type I|NF1]], following evaluation of the mother.<ref>{{cite journal |author=Digilio MC, Sarkozy A, de Zorzi A, ''et al'' |title=LEOPARD syndrome: clinical diagnosis in the first year of life |journal=Am. J. Med. Genet. A |volume=140 |issue=7 |pages=740–6|year=2006 |pmid=16523510 |doi=10.1002/ajmg.a.31156}}</ref> | Diagnosis of Leopard syndrome is sometimes difficult because of the overlap with [[Noonan syndrome]] and [[neurofibromatosis 1]]. In these patients, the presence of the disease can be confirmed with a mutation-based diagnosis, laboratory studies should include molecular analysis of the [[PTPN11]] and [[c-Raf|RAF1]] genes. In a study of 10 infants with clinical indications of Leopard syndrome prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient, with the suspected mutation was subsequently found to have [[Neurofibromatosis type I|NF1]], following evaluation of the mother.<ref>{{cite journal |author=Digilio MC, Sarkozy A, de Zorzi A, ''et al'' |title=LEOPARD syndrome: clinical diagnosis in the first year of life |journal=Am. J. Med. Genet. A |volume=140 |issue=7 |pages=740–6|year=2006 |pmid=16523510 |doi=10.1002/ajmg.a.31156}}</ref> | ||
There are 5 identified [[alleles|allelic]] [[Genetic diversity|variant]]s responsible for Leopard syndrome. Which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than [[transversion]]. | There are 5 identified [[alleles|allelic]] [[Genetic diversity|variant]]s responsible for Leopard syndrome. Which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than [[transversion]]. | ||
Revision as of 20:30, 6 September 2013
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]
Overview
Leopard syndrome is most commonly caused by missense mutations in the PTPN11 gene. It has also been associated with other gene mutations such as RAF1 and BRAF.
Pathophysiology
Genetics
Molecular studies have shown that Leopard syndrome is caused by different missense mutations in PTPN11.[1] Mutations cause a loss of catalytic activity of the SHP2 protein, which is a previously unrecognized behavior for this class of mutations.[2] This interferes with growth factor and related signalling.
In the two predominant mutations of Leopard syndrome, the mutations cause a loss of catalytic activity of the SHP2 protein(the gene product of the PTPN11 gene located at chromosome 12q22-qter), which is a previously unrecognized behavior for this class of mutations.[3] This interferes with growth factor and related signalling. While further research confirms this mechanism,[4][5] additional research is needed to determine how this relates to all of the observed effects of Leopard syndrome.
Associated Conditions
Diagnosis of Leopard syndrome is sometimes difficult because of the overlap with Noonan syndrome and neurofibromatosis 1. In these patients, the presence of the disease can be confirmed with a mutation-based diagnosis, laboratory studies should include molecular analysis of the PTPN11 and RAF1 genes. In a study of 10 infants with clinical indications of Leopard syndrome prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient, with the suspected mutation was subsequently found to have NF1, following evaluation of the mother.[6] There are 5 identified allelic variants responsible for Leopard syndrome. Which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion.
References
- ↑ Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R; et al. (2006). "LEOPARD syndrome: clinical diagnosis in the first year of life". Am J Med Genet A. 140 (7): 740–6. doi:10.1002/ajmg.a.31156. PMID 16523510.
- ↑ Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V; et al. (2006). "Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease". Am J Hum Genet. 78 (2): 279–90. doi:10.1086/499925. PMC 1380235. PMID 16358218.
- ↑ Tartaglia M, Martinelli S, Stella L; et al. (2006). "Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease". Am. J. Hum. Genet. 78 (2): 279–90. doi:10.1086/499925. PMID 16358218.
- ↑ Hanna N, Montagner A, Lee WH; et al. (2006). "Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1". FEBS Lett. 580 (10): 2477–82. doi:10.1016/j.febslet.2006.03.088. PMID 16638574.
- ↑ Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG (2006). "PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects". J. Biol. Chem. 281 (10): 6785–92. doi:10.1074/jbc.M513068200. PMID 16377799.
- ↑ Digilio MC, Sarkozy A, de Zorzi A; et al. (2006). "LEOPARD syndrome: clinical diagnosis in the first year of life". Am. J. Med. Genet. A. 140 (7): 740–6. doi:10.1002/ajmg.a.31156. PMID 16523510.