Alternative titles; symbols
HGNC Approved Gene Symbol: SCYL2
Cytogenetic location: 12q23.1 Genomic coordinates (GRCh38): 12:100,267,177-100,341,715 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q23.1 | Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum | 618766 | Autosomal recessive | 3 |
SCYL2 is a serine/threonine kinase that is expressed in clathrin-coated vesicles (Conner and Schmid, 2005).
By searching for cDNAs encoding large proteins expressed in brain, Nagase et al. (2000) obtained a partial cDNA encoding SCYL2, which they called KIAA1360. The deduced 796-amino acid sequence contains a kinase domain. RT-PCR detected high expression in lung and moderate to high expression in all other adult and fetal tissues and specific brain regions tested.
By directed proteomic and mass spectrometric analysis of adaptor protein preparations from bovine brain, followed by EST database analysis, Conner and Schmid (2005) obtained a full-length cDNA encoding human SCYL2, which they called CVAK104. The deduced 933-amino acid protein has a calculated molecular mass of 104 kD. It contains an N-terminal serine/threonine kinase domain, followed by 2 weak clathrin-binding motifs (DLL), a predicted coiled-coil domain, and an NPF motif that mediates interactions with EPS15 (600051) homology domains. Human CVAK104 shares about 93% amino acid identity with its mouse and rat homologs. Immunoblot analysis of bovine brain lysates detected a 104-kD protein that was predominantly membrane associated and cofractionated with isolated clathrin-coated vesicles. Two other proteins of 116 and 118 kD were present in both cytosol and membrane fractions, but neither associated with clathrin-coated vesicles.
Conner and Schmid (2005) found that human CVAK104 bound directly to both clathrin and the plasma membrane adaptor AP2. Kinase assays showed that CVAK104 phosphorylated itself and the beta-2 adaptin subunit (AP2B1; 601025) of AP2 in a poly(L)-lysine-stimulated manner.
Gross (2015) mapped the SCYL2 to chromosome 12q23.1 based on an alignment of the SCYL2 sequence (GenBank BC063798) with the genomic sequence (GRCh38).
In 2 probands from unrelated consanguineous families of Middle Eastern descent with neurogenic arthrogryposis multiplex congenita-4 with agenesis of the corpus callosum (AMC4; 618766), Seidahmed et al. (2020) identified homozygosity for a nonsense or a frameshift mutation in the SCYL2 gene (616365.0001 and 616365.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Each family had additional patients who were similarly affected, but DNA was not available for study. Functional studies of the variants and studies of patient cells were not performed, but both variants were predicted to result in a loss of SCYL2 function. The authors noted that the patients had both central and peripheral nervous system involvement.
Gingras et al. (2015) found that neuron-specific targeted disruption of the Scyl2 gene in mice resulted in increased perinatal lethality. Mutant mice who survived to adulthood showed growth retardation and severe sensorimotor deficits. The neurologic deficits in these mice were associated with the degeneration of several neuronal populations, most notably CA3 pyramidal neurons of the hippocampus, resulting from excitotoxicity triggered by excessive activation of calcium-permeable glutamate receptors at the synapse. A wide variety of clathrin-mediated functions and lysosomal pathways were preserved in mutant mice, suggesting independent Scyl2 functions. The findings demonstrated an essential role for SCYL2 in regulating neuronal function and survival and suggested a role for SCYL2 in regulating excitatory signaling in the developing brain.
In an 8-month-old male infant (patient 1), born of consanguineous Saudi parents (family 1), with neurogenic arthrogryposis multiplex congenita-4 with agenesis of the corpus callosum (AMC4; 618766), Seidahmed et al. (2020) identified a homozygous c.106C-T transition (c.106C-T, NM_017988.4) in exon 2 of the SCYL2 gene, resulting in an arg36-to-ter (R36X) substitution before the protein kinase domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was filtered against the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a 6-year-old girl (patient 5), born of consanguineous Omani parents (family 2), with neurogenic arthrogryposis multiplex congenita-4 with agenesis of the corpus callosum (AMC4; 618766), Seidahmed et al. (2020) identified a homozygous 1-bp duplication (c.1624dupG, NM_017988.4) in exon 12 of the SCYL2 gene, resulting in a frameshift and premature termination (Val542GlyfsTer16). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database or in an in-house database of 973 ethnically matched controls. There were 3 similarly affected family members, but DNA was not available from these patients. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
Conner, S. D., Schmid, S. L. CVAK104 is a novel poly(L)-lysine-stimulated kinase that targets the beta-2-subunit of AP2. J. Biol. Chem. 280: 21539-21544, 2005. [PubMed: 15809293] [Full Text: https://doi.org/10.1074/jbc.M502462200]
Gingras, S., Earls, L. R., Howell, S., Smeyne, R. J., Zakharenko, S. S., Pelletier, S. SCYL2 protects CA3 pyramidal neurons from excitotoxicity during functional maturation of the mouse hippocampus. J. Neurosci. 35: 10510-10522, 2015. [PubMed: 26203146] [Full Text: https://doi.org/10.1523/JNEUROSCI.2056-14.2015]
Gross, M. B. Personal Communication. Baltimore, Md. 5/15/2015.
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Seidahmed, M., Al-Kindi, A., Alsaif, H. S., Miqdad, A., Alabbad, N., Alfifi, A., Abdelbasit, O. B., Alhussein, K., Alsamadi, A., Ibrahim, N., Al-Futaisi, A., Al-Maawali, A., Alkuyaya, F. S. Recessive mutations in SCYL2 cause a novel syndromic form of arthrogryposis in humans. Hum. Genet. 139: 513-519, 2020. [PubMed: 31960134] [Full Text: https://doi.org/10.1007/s00439-020-02117-7]