Database for pathogenic SH2 domain variations

SH2base - introduction


Basal cell carcinoma

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 (XLP)

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].

ZAP70 deficiency

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 deficiency

  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].

Table 1. Diseases related to SH2 domainsa.

Affected gene







BTK BTK X-linked agammaglobulinemia (XLA) 300300 X-linked 1:200000 in males Hypogammaglobulinemia, antibody deficiency, recurrent bacterial infections
SH2D1A SH2D1A (SAP) X-linked lymphoproliferative disease (XLP) 308240 X-linked 1:1000000 in males Fatal infectious mononucleosis, malignant B cell lymphomas, dysgammaglobulinemia
ZAP70 ZAP-70 Severe combined immunodeficiency (SCID) 600802 Autosomal recessive n.a. Severe pulmonary infection, chronic diarrhea, failure to thrive, persistent candidiasis
PTPN11 SHP-2 Noonan syndrome 163950 Autosomal dominant 1:1000-1:2500 Short stature, facial dysmorphia, wide spectrum of congenital heart defects


SHP-2 Noonan-like / multiple giant-cell lesion syndrome 163955 Autosomal dominant n.a. In addition to main Noonan syndrome phenotypes, giant-cell lesions of bone and soft tissues


SHP-2 Juvenile myelomonocytic leukaemia (JMML) 607785 n.a. n.a. ~30% of myelodysplastic syndrome and 2% of leukaemia patients
PIK3R1 P85α Severe insulin deficiency - n.a. n.a. Acanthosis nigricans, hyperinsulinemia, diabetes mellitus at the later stage
RASA1 RasGAP Basal cell carcinoma (BCC) 605462 Sporadic n.a. Clusters of basal cell carcinoma, development of tumours on the chest
STAT1 STAT1 STAT1 deficiency, complete 600555 n.a. n.a. Susceptibility to viral and intracellular bacterial infections
STAT5B STAT5B Growth hormone insensitivity with immunodeficiency 245590 n.a. n.a. Growth failure, recurrent bacterial and viral infections.

an.a. not available