Alternative titles; symbols
HGNC Approved Gene Symbol: STAMBP
SNOMEDCT: 703369003;
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38) : 2:73,828,961-73,873,656 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.1 | Microcephaly-capillary malformation syndrome | 614261 | Autosomal recessive | 3 |
The STAMBP gene encodes a deubiquitinating (DUB) isopeptidase that has a key role in cell surface receptor-mediated endocytosis and sorting (summary by McDonell et al., 2013).
Signal-transducing adaptor molecule (STAM; 601899) acts downstream of interleukin-2 (IL2; 147680)-induced signaling through JAK3 (600173). It also interacts with JAK2 (147796) after granulocyte-macrophage colony-stimulating factor (GMCSF; 138960) stimulation. STAM contains an SH3 domain that is required for induction of MYC (190080) and cell growth. By Far Western screening of an activated peripheral blood leukocyte cDNA library to identify cDNAs binding to the SH3 domain of STAM, Tanaka et al. (1999) obtained a cDNA encoding AMSH. The deduced 424-amino acid protein contains 2 potential SH3-binding domains (PxxP motifs), a JAB1 (604850) subdomain homologous (JSH) region, and a putative bipartite nuclear localization signal. Northern blot analysis revealed ubiquitous expression of a 2.1-kb AMSH transcript.
Using in situ hybridization and Northern blot analysis, Ishii et al. (2001) observed that Amsh was expressed diffusely in both mantle and ventricular layers throughout the mouse brain at embryonic day 14. By postnatal day 10, Amsh expression was localized to the olfactory bulb, cerebral cortex, hippocampus, and cerebellum.
In transfected COS-7 cells, Kikuchi et al. (2003) found that fluorescence-tagged AMSH was expressed diffusely in the cytoplasm and in a punctate pattern surrounding the nuclear membrane.
By immunoprecipitation and immunoblot analysis, Tanaka et al. (1999) showed that the SH3 domain of STAM was required for AMSH binding at the PxxP motif at pro227 to pro231. Mutation analysis indicated that MYC induction and cell growth were eliminated in the presence of exogenous AMSH lacking the 190 C-terminal residues. Tanaka et al. (1999) concluded that the STAM-AMSH complex plays a critical role in signaling for MYC induction and cell cycle progression downstream of JAK3 and JAK2 after IL2 or GMCSF stimulation.
Using RNF11 (612598) as bait in a yeast 2-hybrid screen of a human ovary cDNA library, Li and Seth (2004) showed that human RNF11 interacted with several proteins, including AMSH. The interaction of RNF11 with AMSH was independent of the RNF11 RING finger domain and PY motif. AMSH was ubiquitinated by the E3 ubiquitin ligase SMURF2 (605532) in the presence of RNF11, and reduction in the steady-state level of AMSH required both RNF11 and SMURF2. Li and Seth (2004) concluded that RNF11 recruits AMSH to SMURF2 for ubiquitination, leading to its degradation by the 26S proteasome.
Using several protein interaction assays, Tsang et al. (2006) showed that AMSH interacted directly with the ESCRT-III components CHMP1B (606486) and CHMP3 (VPS24; 610052). The 3 proteins partially colocalized with M6PR (154540) on late endosomal membranes.
Kikuchi et al. (2003) found that both the nuclear localization signal and the MPN domain of AMSH are required for its nuclear localization. Coimmunoprecipitation analysis of transfected 293T cells showed that epitope-tagged AMSH bound STAM, STAM2 (606244), and GRB2 (108355).
Using FISH, Tanaka et al. (1999) mapped the STAMBP gene to 2p13-p12.
In 10 patients from 9 families with microcephaly-capillary malformation syndrome (MICCAP; 614261), McDonell et al. (2013) identified biallelic mutations in the STAMBP gene (see, e.g., 600247.0001-600247.0007). The mutation types included 6 missense variants, 2 nonsense mutations, 2 frameshift mutations, and 3 intronic mutations. The first mutations were identified by exome sequencing. Some of the patients had previously been reported by Carter et al. (2011), Isidor et al. (2011), and Mirzaa et al. (2011). The phenotype was characterized by severe progressive microcephaly, early-onset refractory epilepsy, profound developmental delay, and multiple small capillary malformations spread diffusely on the body. Additional features, such as dysmorphic facial features and distal limb abnormalities, were also present. Protein studies showed decreased or absent STAMBP protein in mutant cells. Cellular studies by McDonell et al. (2013) showed that siRNA-mediated silencing of STAMBP in human medulloblastoma cells caused increased amounts of conjugated-ubiquitin aggregates; patient lymphocytes showed a similar aggregation that could be rescued by transfection with wildtype STAMBP. The abnormal cellular phenotype was associated with induction of apoptosis and increased autophagic flux. Patient cells also showed increases in the downstream RAS signaling pathway and increased phosphorylation of downstream proteins compared to controls, indicating persistent activation and insensitive active signal transduction, even under starvation conditions. McDonell et al. (2013) hypothesized that the induction of apoptosis may be responsible for microcephaly, whereas overactivation of the RAS pathway may be responsible for the capillary malformations.
Using gene targeting, Ishii et al. (2001) generated Amsh-deficient mice. These mice were indistinguishable from their littermates at birth but exhibited postnatal growth retardation and died between postnatal day 19 (P19) and P23. Histopathologic analysis of brain sections detected a significant loss of neurons and apoptotic cells in the CA1 subfield of the Amsh-deficient hippocampus. Brain atrophy developed by P16 and was accompanied by complete loss of the CA1 neurons in the hippocampus and marked atrophy of the cerebral cortex. Using in vitro primary cultures, Ishii et al. (2001) observed that Amsh-deficient hippocampal neuronal cells were unable to survive in vitro, while Amsh-deficient cerebellar neurons, thymocytes, and embryonic fibroblasts survived normally. They concluded that Amsh is an essential molecule for the survival of neuronal cells in early postnatal mice.
In 2 African American sibs with microcephaly-capillary malformation syndrome (MICCAP; 614261) reported by Mirzaa et al. (2011), McDonell et al. (2013) identified compound heterozygous mutations in the STAMBP gene: a c.125A-G transition, resulting in a glu42-to-gly (E42G) substitution, and a c.532C-T transition, resulting in an arg178-to-ter (R178X; 606247.0002) substitution. The mutations, which were identified by exome sequencing and were not found in several large control exome databases, segregated with the disorder.
For discussion of the arg178-to-ter (R178X) mutation in the STAMBP gene that was found in compound heterozygous state in sibs with microcephaly-capillary malformation syndrome (MICCAP; 614261) by McDonell et al. (2013), see 606247.0001.
In a boy of European descent with microcephaly-capillary malformation syndrome (MICCAP; 614261) reported by Mirzaa et al. (2011), McDonell et al. (2013) identified compound heterozygous mutations in the STAMBP gene: a c.112C-T transition, resulting in an arg38-to-cys (R38C) substitution, and a c.279+5G-T splice site mutation (606247.0004), predicted to include an extra codon in exon 4, supporting a pathogenic effect. The mutations, which were identified by exome sequencing and were not found in several large control exome databases, segregated with the disorder. Another patient of Polynesian descent was compound heterozygous for R38C and a 1-bp deletion (c.411delC; 606247.0007), predicted to result in a frameshift and premature termination (Ile138SerfsTer12).
For discussion of the splice site mutation in the STAMBP gene (c.279+5G-T) that was found in compound heterozygous state in a patient with microcephaly-capillary malformation syndrome (MICCAP; 614261) by McDonell et al. (2013), see 606247.0003.
In a boy of European descent with microcephaly-capillary malformation syndrome (MICCAP; 614261), McDonell et al. (2013) identified a homozygous c.1270C-T transition in the STAMBP gene, resulting in an arg424-to-ter (R424X) substitution. Analysis of parental DNA showed that the homozygosity was due to maternal isodisomy of chromosome 2. An unrelated patient was compound heterozygous for the R424X mutation and a c.299T-A transversion, resulting in a phe100-to-tyr (F100Y; 606247.0006) substitution. Both patients had previously been reported by Carter et al. (2011).
For discussion of the phe100-to-tyr (F100Y) mutation in the STAMBP gene that was found in compound heterozygous state in a patient with microcephaly-capillary malformation syndrome (MICCAP; 614261) by McDonell et al. (2013), see 606247.0005.
For discussion of the 1-bp deletion in the STAMBP gene (c.411delC) that was found in compound heterozygous state in a patient with microcephaly-capillary malformation syndrome (MICCAP; 614261) by McDonell et al. (2013), see 606247.0003.
Carter, M. T., Geraghty, M. T., De La Cruz, L., Reichard, R. R., Boccuto, L., Schwartz, C. E., Clericuzio, C. L. A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies. Am. J. Med. Genet. 155A: 301-306, 2011. [PubMed: 21271646] [Full Text: https://doi.org/10.1002/ajmg.a.33841]
Ishii, N., Owada, Y., Yamada, M., Miura, S., Murata, K., Asao, H., Kondo, H., Sugamura, K. Loss of neurons in the hippocampus and cerebral cortex of AMSH-deficient mice. Molec. Cell. Biol. 21: 8626-8637, 2001. [PubMed: 11713295] [Full Text: https://doi.org/10.1128/MCB.21.24.8626-8637.2001]
Isidor, B., Barbarot, S., Beneteau, C., Le Caignec, C., David, A. Multiple capillary skin malformations, epilepsy, microcephaly, mental retardation, hypoplasia of the distal phalanges: report of a new case and further delineation of a new syndrome. (Letter) Am. J. Med. Genet. 155A: 1458-1460, 2011. [PubMed: 21548128] [Full Text: https://doi.org/10.1002/ajmg.a.34048]
Kikuchi, K., Ishii, N., Asao, H., Sugamura, K. Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. Biochem. Biophys. Res. Commun. 306: 637-643, 2003. [PubMed: 12810066] [Full Text: https://doi.org/10.1016/s0006-291x(03)01009-x]
Li, H., Seth, A. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein. Oncogene 23: 1801-1808, 2004. [PubMed: 14755250] [Full Text: https://doi.org/10.1038/sj.onc.1207319]
McDonell, L. M., Mirzaa, G. M., Alcantara, D., Schwartzentruber, J., Carter, M. T., Lee, L. J., Clericuzio, C. L., Graham, J. M., Jr., Morris-Rosendahl, D. J., Polster, T., Acsadi, G., Townshend, S., and 19 others. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nature Genet. 45: 556-562, 2013. [PubMed: 23542699] [Full Text: https://doi.org/10.1038/ng.2602]
Mirzaa, G. M., Paciorkowski, A. R., Smyser, C. D., Willing, M. C., Lind, A. C., Dobyns, W. B. The microcephaly-capillary malformation syndrome. Am. J. Med. Genet. 155A: 2080-2087, 2011. [PubMed: 21815250] [Full Text: https://doi.org/10.1002/ajmg.a.34118]
Tanaka, N., Kaneko, K., Asao, H., Kasai, H., Endo, Y., Fujita, T., Takeshita, T., Sugamura, K. Possible involvement of a novel STAM-associated molecule 'AMSH' in intracellular signal transduction mediated by cytokines. J. Biol. Chem. 274: 19129-19135, 1999. [PubMed: 10383417] [Full Text: https://doi.org/10.1074/jbc.274.27.19129]
Tsang, H. T. H., Connell, J. W., Brown, S. E., Thompson, A., Reid, E., Sanderson, C. M. A systematic analysis of human CHMP protein interactions: additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex. Genomics 88: 333-346, 2006. [PubMed: 16730941] [Full Text: https://doi.org/10.1016/j.ygeno.2006.04.003]