| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Costello syndrome and CFC syndrome are rare, multiple congenital anomaly syndrome characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities and mental retardation. Clinical features with both syndromes overlap with those with Noonan syndrome. Gain-of-function mutations in PTPN11 have been identified in approximately 50% of individuals with clinically diagnosed Noonan syndrome(Tartaglia et al., 2001) SHP-2, the product of PTPN11, is a widely expressed cytoplasmic tyrosine phosphatase and has been implicated in signal transduction pathways elicited by growth factors, cytokines, hormones and extracellular matrix. No PTPN11 mutations have been found in individuals with Costello or CFC syndrome and genetic causes for these disorders had been unknown.
We hypothesized that genes mutated in Costello syndrome and in PTPN11-negative Noonan syndrome encode molecules that function upstream or downstream of SHP-2 in signal pathways. Among these molecules, they sequenced the entire coding region of 4 RAS (KRAS, HRAS and NRAS, as well as the recently identified ERAS genes) in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN//-negative Noonan syndrome. We discovered HRAS germline mutations in patients with Costello syndrome, a congenital anomaly/mental retardation syndrome (Aoki et al. 2005). This discovery provided a clue to identification of germline mutations in KRAS, BRAF and MAP2K1/2 mutations in patients with cardio-facio-cutaneous (CFC) syndrome (Niihori et al. 2006 and Narumi et al. 2007). These genes encode molecules in the RAS/RAF/MEK/ERK pathway, proposing a new concept that clinically related disorders, Noonan, Costello and CFC are caused by dys-regulation of RAS/RAF/MEK/ERK pathway.
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