Noonan syndrome causes: Difference between revisions
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{{Patient}} | {{Patient}} | ||
{{CMG}} | {{CMG}} {{AE}} [[User:Sergekorjian|Serge Korjian]], [[User:YazanDaaboul|Yazan Daaboul]] | ||
==Overview== | ==Overview== | ||
Most cases of Noonan syndrome have an autosomal dominant inheritance pattern and have been associated with either one of eight genes all involved in the RAS/MAP kinase pathway. In order of prevalence, the causative mutations involve the following genes: PTPN11, SOS1, RAF1, SHOC2, KRAS, BRAF, NRAS, and CBL. | |||
==Causes== | ==Causes== | ||
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with [[autosomal dominant]]inheritance and variable expression. Mutations in the [[Ras subfamily|Ras]]/[[Mitogen-activated protein kinase|MAPK]] signaling pathways are known to be responsible for ~70% of NS cases.<ref name=Razzaque2012>Razzaque MA, Komoike Y, Nishizawa T, Inai K, Furutani M, Higashinakagawa T, Matsuoka R (2012) Characterization of a novel KRAS mutation identified in Noonan syndrome. Am J Med Genet A{{doi|10.1002/ajmg.a.34419}}.</ref> | |||
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with [[autosomal dominant]]inheritance and variable expression. Mutations in the [[Ras subfamily|Ras]]/[[ | |||
A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities: | A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities: | ||
# | # Manifestations are variably expressed and could be so subtle as to go unrecognized ([[Expressivity#variable expressivity|variable xpressivity]]) | ||
# | # A high proportion of cases represent new, sporadic [[mutation]]s | ||
# Noonan syndrome is [[heterogeneous]], comprising more than one similar condition of differing cause, some not inherited. | # Noonan syndrome is [[heterogeneous]], comprising more than one similar condition of differing cause, some not inherited. | ||
{| | |||
A number of inheritable mutations can be responsible for Noonan syndrome, most notably mutations of the PTPN11 gene on chromosome 12 seen in more than half of the patients. Almost all causative mutations seen in the PTPN11 gene are missense changes. The single most common mutation in PTPN11 accounting for 25% of cases of Noonan sydrome is an A-to-G transition at nucleotide 922. In order of prevalence, the causative mutations involve the following genes: PTPN11, SOS1, RAF1, SHOC2, KRAS, BRAF, NRAS, and CBL. Below is a table that details some common genetic loci involved. <ref name="pmid16124853">{{cite journal| author=Tartaglia M, Gelb BD| title=Noonan syndrome and related disorders: genetics and pathogenesis. | journal=Annu Rev Genomics Hum Genet | year= 2005 | volume= 6 | issue= | pages= 45-68 | pmid=16124853 | doi=10.1146/annurev.genom.6.080604.162305 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16124853 }} </ref> | |||
{| border="1" style="border-collapse:collapse; text-align:center; font-size:120%;" cellpadding="5" align="center" width="900px" | |||
|- | |- | ||
! Type | ! bgcolor="#67e1ff"| Type | ||
! [[OMIM]] | ! bgcolor="#67e1ff"|[[OMIM]] | ||
! Gene | ! bgcolor="#67e1ff"|Gene | ||
! Description | ! bgcolor="#67e1ff"|Description | ||
|- | |- | ||
| NS1 | | bgcolor="#f3f3f3"|NS1 | ||
| {{OMIM2|163950}} | | bgcolor="#f3f3f3"|{{OMIM2|163950}} | ||
| [[PTPN11]] | | bgcolor="#f3f3f3"|[[PTPN11]] | ||
| In most of the families with multiple affected members, NS maps to [[Chromosome 12 (human)|chromosome 12]]q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the ''PTPN11'' gene at that location, which encodes protein tyrosine phosphatase SHP-2.<ref>{{cite journal |author=Tartaglia M, Mehler EL, Goldberg R, ''et al'' |title=Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome |journal=Nat. Genet. |volume=29 |issue=4 |pages=465–8 |year=2001|pmid=11704759 |doi=10.1038/ng772}} | | In most of the families with multiple affected members, NS maps to [[Chromosome 12 (human)|chromosome 12]]q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the ''PTPN11'' gene at that location, which encodes protein tyrosine phosphatase SHP-2.<ref>{{cite journal |author=Tartaglia M, Mehler EL, Goldberg R, ''et al'' |title=Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome |journal=Nat. Genet. |volume=29 |issue=4 |pages=465–8 |year=2001|pmid=11704759 |doi=10.1038/ng772}}</ref> | ||
|- | |- | ||
| NS2 | | bgcolor="#f3f3f3"|NS2 | ||
| {{OMIM2|605275}} | | bgcolor="#f3f3f3"|{{OMIM2|605275}} | ||
| unknown (autosomal recessive)<ref>{{cite pmid|10982482}}</ref> | | bgcolor="#f3f3f3"|unknown (autosomal recessive)<ref>{{cite pmid|10982482}}</ref> | ||
| | | | ||
|- | |- | ||
| NS3 | | bgcolor="#f3f3f3"|NS3 | ||
| {{OMIM2|609942}} | | bgcolor="#f3f3f3"|{{OMIM2|609942}} | ||
| [[KRAS]] | | bgcolor="#f3f3f3"|[[KRAS]] | ||
| Additional mutations in KRAS <ref>{{cite journal |author=Schubbert S, Zenker M, Rowe SL, ''et al'' |title=Germline KRAS mutations cause Noonan syndrome |journal=Nat. Genet. |volume=38 |issue=3 |pages=331–6 |year=2006 |pmid=16474405 |doi=10.1038/ng1748}}</ref> genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. | | Additional mutations in KRAS <ref>{{cite journal |author=Schubbert S, Zenker M, Rowe SL, ''et al'' |title=Germline KRAS mutations cause Noonan syndrome |journal=Nat. Genet. |volume=38 |issue=3 |pages=331–6 |year=2006 |pmid=16474405 |doi=10.1038/ng1748}}</ref> genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. | ||
|- | |- | ||
| NS4 | | bgcolor="#f3f3f3"|NS4 | ||
| {{OMIM2|610733}} | | bgcolor="#f3f3f3"|{{OMIM2|610733}} | ||
| [[SOS1]] | | bgcolor="#f3f3f3"|[[SOS1]] | ||
| It has recently been shown that activating mutations in [[SOS1]] also give rise to NS.<ref>{{cite journal |author=Roberts AE, Araki T, Swanson KD, ''et al'' |title=Germline gain-of-function mutations in SOS1 cause Noonan syndrome |journal=Nat. Genet. |volume=39 |issue=1|pages=70–4 |year=2007 |pmid=17143285 |doi=10.1038/ng1926}}</ref> Shp2 and SOS1 both have roles as positive regulators of the [[Ras subfamily|Ras]]/[[MAP kinase]] pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.<ref>{{cite journal |author=Bentires-Alj M, Kontaridis MI, Neel BG |title=Stops along the RAS pathway in human genetic disease |journal=Nat. Med. |volume=12 |issue=3 |pages=283–5 |year=2006 |pmid=16520774 |doi=10.1038/nm0306-283}}</ref> | | It has recently been shown that activating mutations in [[SOS1]] also give rise to NS.<ref>{{cite journal |author=Roberts AE, Araki T, Swanson KD, ''et al'' |title=Germline gain-of-function mutations in SOS1 cause Noonan syndrome |journal=Nat. Genet. |volume=39 |issue=1|pages=70–4 |year=2007 |pmid=17143285 |doi=10.1038/ng1926}}</ref> Shp2 and SOS1 both have roles as positive regulators of the [[Ras subfamily|Ras]]/[[MAP kinase]] pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.<ref>{{cite journal |author=Bentires-Alj M, Kontaridis MI, Neel BG |title=Stops along the RAS pathway in human genetic disease |journal=Nat. Med. |volume=12 |issue=3 |pages=283–5 |year=2006 |pmid=16520774 |doi=10.1038/nm0306-283}}</ref> | ||
|- | |- | ||
| NS5 | | bgcolor="#f3f3f3"|NS5 | ||
| {{OMIM2|611553}} | | bgcolor="#f3f3f3"|{{OMIM2|611553}} | ||
| [[RAF1]] | | bgcolor="#f3f3f3"|[[RAF1]] | ||
| Additional mutations in ''RAF1''<ref>{{cite journal |author=Razzaque MA, Nishizawa T, Komoike Y, ''et al'' |title=Germline gain-of-function mutations in ''RAF1'' cause Noonan syndrome |journal=Nat. Genet. |volume=39 |issue=8 |pages=1013–7 |year=2007 |pmid=17603482|doi=10.1038/ng2078}}</ref> genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. | | Additional mutations in ''RAF1''<ref>{{cite journal |author=Razzaque MA, Nishizawa T, Komoike Y, ''et al'' |title=Germline gain-of-function mutations in ''RAF1'' cause Noonan syndrome |journal=Nat. Genet. |volume=39 |issue=8 |pages=1013–7 |year=2007 |pmid=17603482|doi=10.1038/ng2078}}</ref> genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. | ||
|} | |} | ||
==References== | ==References== | ||
Latest revision as of 02:15, 15 November 2013
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul
Overview
Most cases of Noonan syndrome have an autosomal dominant inheritance pattern and have been associated with either one of eight genes all involved in the RAS/MAP kinase pathway. In order of prevalence, the causative mutations involve the following genes: PTPN11, SOS1, RAF1, SHOC2, KRAS, BRAF, NRAS, and CBL.
Causes
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominantinheritance and variable expression. Mutations in the Ras/MAPK signaling pathways are known to be responsible for ~70% of NS cases.[1]
A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
- Manifestations are variably expressed and could be so subtle as to go unrecognized (variable xpressivity)
- A high proportion of cases represent new, sporadic mutations
- Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.
A number of inheritable mutations can be responsible for Noonan syndrome, most notably mutations of the PTPN11 gene on chromosome 12 seen in more than half of the patients. Almost all causative mutations seen in the PTPN11 gene are missense changes. The single most common mutation in PTPN11 accounting for 25% of cases of Noonan sydrome is an A-to-G transition at nucleotide 922. In order of prevalence, the causative mutations involve the following genes: PTPN11, SOS1, RAF1, SHOC2, KRAS, BRAF, NRAS, and CBL. Below is a table that details some common genetic loci involved. [2]
| Type | OMIM | Gene | Description |
|---|---|---|---|
| NS1 | 163950 | PTPN11 | In most of the families with multiple affected members, NS maps to chromosome 12q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2.[3] |
| NS2 | 605275 | unknown (autosomal recessive)[4] | |
| NS3 | 609942 | KRAS | Additional mutations in KRAS [5] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. |
| NS4 | 610733 | SOS1 | It has recently been shown that activating mutations in SOS1 also give rise to NS.[6] Shp2 and SOS1 both have roles as positive regulators of the Ras/MAP kinase pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.[7] |
| NS5 | 611553 | RAF1 | Additional mutations in RAF1[8] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. |
References
- ↑ Razzaque MA, Komoike Y, Nishizawa T, Inai K, Furutani M, Higashinakagawa T, Matsuoka R (2012) Characterization of a novel KRAS mutation identified in Noonan syndrome. Am J Med Genet Adoi:10.1002/ajmg.a.34419.
- ↑ Tartaglia M, Gelb BD (2005). "Noonan syndrome and related disorders: genetics and pathogenesis". Annu Rev Genomics Hum Genet. 6: 45–68. doi:10.1146/annurev.genom.6.080604.162305. PMID 16124853.
- ↑ Tartaglia M, Mehler EL, Goldberg R; et al. (2001). "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome". Nat. Genet. 29 (4): 465–8. doi:10.1038/ng772. PMID 11704759.
- ↑ PMID 10982482 (PMID 10982482)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ Schubbert S, Zenker M, Rowe SL; et al. (2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6. doi:10.1038/ng1748. PMID 16474405.
- ↑ Roberts AE, Araki T, Swanson KD; et al. (2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome". Nat. Genet. 39 (1): 70–4. doi:10.1038/ng1926. PMID 17143285.
- ↑ Bentires-Alj M, Kontaridis MI, Neel BG (2006). "Stops along the RAS pathway in human genetic disease". Nat. Med. 12 (3): 283–5. doi:10.1038/nm0306-283. PMID 16520774.
- ↑ Razzaque MA, Nishizawa T, Komoike Y; et al. (2007). "Germline gain-of-function mutations in RAF1 cause Noonan syndrome". Nat. Genet. 39 (8): 1013–7. doi:10.1038/ng2078. PMID 17603482.