Somatic mutations at the phosphotyrosine-binding pocket of the C-terminal SH2 domain of GTPase-activating protein RASA1 have been found in a subset of Basal-cell carcinoma (BCC) [Friedman, 1995]. RASA1 acts by enhancing the intrinsic GTPase activity of Ras, leading to hydrolysis of bound GTP to GDP and down regulation of Ras activity [Gold, et al., 1993; Scheffzek, et al., 1998]. BCC is the most frequent skin cancer in the white population [Miller, 1991]. The structural information of the RasGap SH2 domains is currently unavailable.
X-linked agammaglobulinemia (XLA)
X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations
in the gene coding for Bruton's tyrosine kinase (BTK) [Väliaho et al.,
2006]. Patients with XLA have decreased number of mature B cells and lack
of all immunoglobulin isotypes causing susceptibility to severe bacterial
infections [Reviewed in Lindvall et al., 2005].
X-linked lymphoproliferative disease
X-linked lymphoproliferative (XLP) syndrome is a primary immunodeficiency
marked by a patient's inability to control acute Epstein Barr virus infection.
The pathogenic condition has various phenotypes, including fulminant infectious
mononucleosis, dysgammaglobulinemia and malignant B cell lymphomas [Purtilo
et al., 1977; Coffey et al., 1998]. XLP patients exhibit immune defects such
as abnormal natural killer and T cell mediated cytotoxicity. The gene affected
encodes a SH2D1A protein consisting only of a SH2 domain and a short C-terminal
tail [Sayos et al., 1998].
ZAP-70 deficiency is a rare autosomal recessive form of severe combined immunodeficiency (SCID) caused by mutations in the gene coding for T cell receptor z-chain associated protein kinase [ Chan et al., 1994] . Patients with ZAP-70 deficiency have the selective absence of CD8+ T cells and abundant CD4+ T cells in peripheral blood.
The loss of ZAP-70 function leads to selective inability to produce CD8+ T lymphocytes and abolishes T cell receptor stimulation in mature CD4+ T lymphocytes [Arpaia, et al., 1994; Elder, et al., 1994].
Noonan syndrome (NS)
Noonan syndrome (NS) is caused by mutations
in PTPN11 , a gene encoding the nonreceptor protein tyrosine
phosphatase SHP2. These mutations account for about half of the
NS patients [Tartaglia et al., 2001]. Another forms of Noonan syndrome
are caused by mutations in theKRAS [Schubbert
et al., 2006] , SOS1 [Roberts et al., 2007] and NF1 [DeLuca
et al., 2005] genes.
The clinical features include short stature, facial dysmorphia, pulmonary valve stenosis, pectus deformities and webbed or short neck. Less prevalent findings include cryptorchidism in affected boys, mental retardation, bleeding diatheses and hematopoietic abnormalities including certain leukemias [Gelb & Tartaglia, 2006].
Juvenile myelomonocytic leukaemia (JMML)
JMML is a myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukaemia [ Hasle et al., 1999 ]. Germline mutations in PTPN11 lead to Noonan syndrome associated with JMML, and somatic PTPN11 mutations are associated with isolated JMML [Tartaglia et al., 2003]. The disorder can also be caused by mutations in NRAS , KRAS2 , NF1 , or GRAF .
Severe insulin deficiency
Mutations in the PIK3R1 gene encoding phosphatidylinositol 3-kinase (PI3-kinase) have been found to cause severe insulin resistance [Baynes et al., 2000]. The kinase acts as a key step in the metabolic actions of insulin, such as insulin-stimulated increase in glucose uptake, and glycogen synthesis in insulin-sensitive tissues [Holman & Kasuga, 1997; Shepherd et al., 1998].
STAT1 mediates interferon signalling
as a part of the JAK-STAT1-pathway [Zhu et al., 1997]. Mutations
in the STAT1 gene cause complete STAT1 deficiency. The disease phenotype is characterized by an impaired response to IFN-γ, leading to severe viral disease and mycobacteriosis [Dupuis et al., 2003].
Growth hormone insensitivity with immunodeficiency
STAT5B acts as a part of the growth hormone signalling pathway leading to stimulation of insulin-like growth factor I (IGF-I) gene transcription [Woelfle et al., 2003]. The absence of STAT5B is associated with diminished post-natal growth, as demonstrated by mouse knockout models [Udy et al., 1997; Teglund et al., 1998], and mutations in the STAT5B SH2 domain in humans lead to growth hormone insensitivity with immunodeficiency [Kofoed et al., 2003].