Noonan syndrome causes
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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), or
- a high proportion of cases represent new, sporadic mutations, or
- Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.
| 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.[2] The SHP2 protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves. Chromosomal abnormalities, such as a duplication of chromosome region 12q24 encompassing gene PTPN11 can result in an apparent Noonan syndrome.[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. |
A condition known as "neurofibromatosis-Noonan syndrome" is associated with neurofibromin.[9]
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, 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.
- ↑ Shchelochkov OA et al, Am J Med Genet A, 2008 Apr 15;146A(8):1042-8
- ↑ 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.
- ↑ PMID 16380919 (PMID 16380919)
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