Alternative titles; symbols
HGNC Approved Gene Symbol: ANO6
SNOMEDCT: 128098009;
Cytogenetic location: 12q12 Genomic coordinates (GRCh38) : 12:45,216,095-45,440,404 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q12 | Scott syndrome | 262890 | Autosomal recessive | 3 |
Transmembrane protein 16F (TMEM16F) is an essential component for the Ca(2+)-dependent exposure of phosphatidylserine on the platelet surface, necessary to trigger the clotting system (Suzuki et al., 2010).
By searching databases for sequences similar to TMEM16A (610108), Katoh and Katoh (2004) identified TMEM16F. The deduced 892-amino acid protein contains 8 transmembrane domains. The N and C termini are cytoplasmic, and the extracellular regions contain 6 putative N-glycosylation sites. TMEM16F and TMEM16E (608662) share 50.3% amino acid identity. By EST database analysis, Katoh and Katoh (2004) determined that TMEM16F is expressed in embryonic stem cells, fetal liver, retina, chronic myelogenous leukemia, and intestinal cancer.
Katoh and Katoh (2004) determined that the TMEM16F gene contains 20 exons and spans more than 119.7 kb.
By genomic sequence analysis, Katoh and Katoh (2004) mapped the TMEM16F gene to chromosome 12q12, where it is linked to the NELL2 gene (602320). This locus is paralogous to the NELL1 (602319)-TMEM16E locus on chromosome 11p15.1-p14.3. Katoh and Katoh (2004) also mapped the mouse Tmem16f gene to chromosome 15E3.
Suzuki et al. (2010) showed that TMEM16F is an essential component for the Ca(2+)-dependent exposure of phosphatidylserine on the cell surface. When a mouse B-cell line, Ba/F3, was treated with a Ca(2+) ionophore under low Ca(2+) conditions, it reversibly exposed phosphatidylserine. Using this property, Suzuki et al. (2010) established a Ba/F3 subline that strongly exposed phosphatidylserine by repetitive fluorescence-activated cell sorting. A cDNA library was constructed from the subline, and a cDNA that caused Ba/F3 to expose phosphatidylserine spontaneously was identified by expression cloning. The cDNA encoded a constitutively active mutant of TMEM16F, a protein with 8 transmembrane segments. Wildtype TMEM16F was localized on the plasma membrane and conferred Ca(2+)-dependent scrambling of phospholipids.
Suzuki et al. (2010) found that a patient with Scott syndrome (SCTS; 262890) was homozygous for a splice-acceptor mutation at intron 12 of TMEM16F, resulting in loss of exon 13. This exon skipping led to premature termination in exon 14. Using RT/PCR, the sample from the patient showed both exon skipping and reduced amount of transcript.
In 2 sibs with Scott syndrome, Boisseau et al. (2018) identified compound heterozygous mutations in the ANO6 gene (608663.0002-608663.0003). The mutations were identified by Sanger sequencing of the ANO6 gene and copy number analysis from next-generation sequencing data.
By sequencing of the ANO6 gene in a 64-year-old woman with Scott syndrome, Castoldi et al. (2011) identified compound heterozygous mutations (608663.0004-608773.0005).
In a 36-year-old Moroccan woman with Scott syndrome, Bouchaib et al. (2023) identified homozygosity for a nonsense mutation in the ANO6 gene (R440X; 608663.0006).
In B-cell lines established from a patient with Scott syndrome (SCTS; 262890) by Kojima et al. (1994), Suzuki et al. (2010) identified homozygosity for a G-to-T transversion at the -1 position of exon 13 of the TMEM16F gene, at the splice acceptor site of intron 12. Both parents were heterozygous for the mutation. Sequencing of the cDNA showed that the patient lacked 226 basepairs of sequence corresponding to exon 13. This skipping of exon 13 caused a frameshift resulting in the premature termination of the protein in exon 14 at the third transmembrane segment of human TMEM16F.
In 2 sibs with Scott syndrome (SCTS; 262890), Boisseau et al. (2018) identified compound heterozygosity for 2 mutations in the ANO6 gene: a c.889C-T transition, resulting in an arg297-to-ter (R297X) substitution, and a deletion of exons 1 to 10 (608663.0003). The mutations were identified by Sanger sequencing of the ANO6 gene and copy number analysis from next-generation sequencing data. Ionophore activation of platelets from the patients demonstrated low phosphatidylserine expression compared to controls.
For discussion of the deletion of exons 1 to 10 of the ANO6 gene that was identified in compound heterozygous state in 2 sibs with Scott syndrome (SCTS; 262890) by Boisseau et al. (2018), see 608663.0002.
In a 64-year-old woman with Scott syndrome (SCTS; 262890), Castoldi et al. (2011) identified compound heterozygous mutations in the ANO6 gene: an IVS6+1G-A transition, resulting in a splicing abnormality, and a 1-bp insertion (c.1219insT; 608663.0005), predicted to result in a frameshift and premature termination. The mutations, which were identified by sequencing of the ANO6 gene, were not present in 100 controls. Analysis of cDNA in leukocytes from the patient demonstrated that the mutation resulted in skipping of exon 6.
For discussion of the 1-bp insertion (c.1219insT) in the ANO6 gene that was identified in compound heterozygous state in a woman with Scott syndrome (SCTS; 262890) by Castoldi et al. (2011), see 608663.0004.
In a 36-year-old Moroccan woman with Scott syndrome (SCTS; 262890), Bouchaib et al. (2023) identified homozygosity for a c.1318C-T transition in the ANO6 gene, resulting in an arg440-to-ter (R440X) substitution. The proband's parents were consanguineous; their mutation status was not reported.
Boisseau, P., Bene, M. C., Besnard, T., Pachchek, S., Giraud, M., Talarmain, P., Robillard, N., Gourlaouen, M. A., Bezieau, S., Fouassier, M. A new mutation of ANO6 in two familial cases of Scott syndrome. Brit. J. Haemat. 180: 750-752, 2018. [PubMed: 27879994] [Full Text: https://doi.org/10.1111/bjh.14439]
Bouchaib, A. E., Balde, M. A., Babahabib, A., Elhassani, M. E. M., Kouach, J. Syndrome de Scott et grossesse: a propos d'un cas. Pan Afr. Med. J. 44: 151, 2023. [PubMed: 37455884] [Full Text: https://doi.org/10.11604/pamj.2023.44.151.38361]
Castoldi, E., Collins, P. W., Williamson, P. L., Bevers, E. M. Compound heterozygosity for 2 novel TMEM16F mutations in a patient with Scott syndrome. Blood 117: 4399-4400, 2011. [PubMed: 21511967] [Full Text: https://doi.org/10.1182/blood-2011-01-332502]
Katoh, M., Katoh, M. Identification and characterization of TMEM16E and TMEM16F genes in silico. Int. J. Oncol. 24: 1345-1349, 2004. [PubMed: 15067359]
Kojima, H., Newton-Nash, D., Weiss, H. J., Zhao, J., Sims, P. J., Wiedmer, T. Production and characterization of transformed B-lymphocytes expressing the membrane defect of Scott syndrome. J. Clin. Invest. 94: 2237-2244, 1994. [PubMed: 7989579] [Full Text: https://doi.org/10.1172/JCI117586]
Suzuki, J., Umeda, M., Sims, P. J., Nagata, S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468: 834-838, 2010. [PubMed: 21107324] [Full Text: https://doi.org/10.1038/nature09583]