* 602572
ANNEXIN A11; ANXA11
Alternative titles; symbols
ANNEXIN XI; ANX11
AUTOANTIGEN, 56-KD
HGNC Approved Gene Symbol: ANXA11
Cytogenetic location: 10q22.3 Genomic coordinates (GRCh38): 10:80,153,952-80,205,676 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 10q22.3 | Amytrophic lateral sclerosis 23 | 617839 | Autosomal dominant | 3 |
TEXT
Description
The ANXA11 gene encodes a member of the annexin family of calcium-dependent phospholipid-binding proteins. Each annexin family member has a unique N-terminal domain and 4 highly conserved C-terminal annexin domains, which can form complexes with calcium ions, thus facilitating binding to anionic cell membranes. ANXA11 has the longest N terminus, which is hydrophobic and disordered and binds to several interacting partners, the best characterized being calcyclin (S100A6; 114110) (summary by Smith et al., 2017).
Cloning and Expression
To identify a 56-kD antigen recognized by sera from patients with autoimmune diseases, Misaki et al. (1994) screened a human teratocarcinoma cDNA expression library with the anti-56-kD antigen autoantibodies. They isolated a cDNA predicting a 505-amino acid protein with 60% identity to other annexins in the conserved C-terminal domain and 92.5% identity to bovine annexin XI over the entire protein. Misaki et al. (1994) concluded that the 56-kD autoantigen is human annexin XI, or ANXA11.
Smith et al. (2017) found expression of the Anxa11 gene in the nucleus and cytoplasm of mouse primary motor neurons. In the cytoplasm, it was present in larger vesicle-like structures and smaller foci structures, and was diffusely distributed throughout the soma, axons, and dendrites. The findings suggested a role in vesicular transport.
Gene Structure
Bances et al. (2000) determined that the mouse Anxa11 gene contains 15 exons and spans 40 kB. Exon 1 is untranslated, and intron 1 spans about 20 kb. The human ANXA11 gene has the same general structure as the mouse gene; however, EST database analysis indicated that human ANXA11 transcripts also use variably spliced exons 1b and 1c, which can lengthen the 5-prime UTR. The intronic sequences of the mouse and human ANXA11 genes contain several types of repetitive elements, including retroviral long terminal repeats. The mouse promoter region contains a remnant LINE-1 insertion not found in the human gene. The 5-prime flanking region of the ANXA11 gene contains a CpG island and MYOD (159970), SP1 (189906), and glucocorticoid response elements, but no proximal TATA or CAAT boxes.
Molecular Genetics
Amyotrophic Lateral Sclerosis 23
In 10 patients from 7 unrelated families with amyotrophic lateral sclerosis-23 (ALS23; 617839), Smith et al. (2017) identified 4 different heterozygous missense mutations in the ANXA11 gene (see, e.g., D40G, 602572.0001; G38R, 602572.0002; and G175R, 602572.0003). Three patients with sporadic ALS were also found to carry heterozygous missense variants (D40G, G189E, and R235Q). The mutations were found by whole-exome sequencing of 751 probands with familial ALS (FALS) and direct sequencing of the ANXA11 gene in 180 patients with sporadic ALS. (Elsewhere in the paper, the FALS cohort is noted to include 694 probands). One recurrent mutation, D40G, was found in 3 families and in 1 patient with sporadic ALS; haplotype analysis suggested that the mutation arose on a European background. Four of the 6 mutations identified clustered in the long N terminus, suggesting functional importance. Postmortem tissue available from a patient with the D40G mutation showed classic pathologic features of ALS and large neuronal cytoplasmic ANXA11-immunoreactive inclusions in the spinal cord and certain brain regions, including the motor cortex and occipital lobe. These aggregates formed skein-like, tubular-shaped, filamentous, and complex basket-like structures. These inclusions did not colocalize with TDP43. ANXA11 inclusions were not observed in controls or in patients with other neurodegenerative disorders. Overexpression of mutant ANXA11 in mouse and human cells showed that the R235Q mutant caused increased aggregation, whereas other variants did not. R235Q sequestered wildtype ANXA11 into inclusions, consistent with a dominant-negative effect. Calcyclin binding was inhibited by the D40G, G189E, and R235Q mutations, but was increased by the G38R mutation compared to wildtype. Smith et al. (2017) speculated that loss of calcyclin binding may result in an accumulation of cytoplasmic annexin A11, promoting formation of insoluble aggregates and likely disrupting intracellular protein trafficking.
Associations Pending Confirmation
For discussion of a possible association between variation in the ANXA11 gene and susceptibility to sarcoidosis, see SS3 (612388).
Mapping
Morgan et al. (1998) mapped the ANXA11 gene to 10q22.3-q23.1 by fluorescence in situ hybridization.
By genomic sequence analysis, Bances et al. (2000) mapped the mouse Anxa11 gene to chromosome 14.
ALLELIC VARIANTS 3 Selected Examples):
.0001 AMYOTROPHIC LATERAL SCLEROSIS 23
In 5 members from 3 unrelated European families with amyotrophic lateral sclerosis-23 (ALS23; 617839), Smith et al. (2017) identified a heterozygous A-to-G transition (chr10.81,930,608A-G, GRCh37) in the ANXA11 gene, resulting in an asp40-to-gly (D40G) substitution at a conserved residue. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Several unaffected family members carried the mutation, consistent with incomplete penetrance. Haplotype analysis of British mutation carriers suggested a founder effect. Subsequently, an unrelated patient (patient 10) with sporadic ALS was also found to carry the D40G mutation. This latter patient was identified from a cohort of 180 patients with sporadic disease who underwent direct sequencing of the ANXA11 gene. Statistical analysis demonstrated an association between the D40G variant and ALS (p = 0.0102).
.0002 AMYOTROPHIC LATERAL SCLEROSIS 23
In 2 unrelated probands with familial amyotrophic lateral sclerosis-23 (ALS23; 617839), Smith et al. (2017) identified a heterozygous c.112G-A transition (c.112G-A, NM_145869) in the ANXA11 gene, resulting in a gly38-to-arg (G38R) substitution at a conserved residue in the N terminus. The variant was not found in 4,505 local control exomes, but was found in 5 of 31,804 exomes in the ExAC database.
.0003 AMYOTROPHIC LATERAL SCLEROSIS 23
In 2 sibs with late-onset familial amyotrophic lateral sclerosis-23 (ALS23; 617839), Smith et al. (2017) identified a heterozygous c.523G-A transition (c.523G-A, NM_145869) in the ANXA11 gene, resulting in a gly175-to-arg (G175R) substitution at a conserved residue in the N terminus. The patients had onset of the disorder in their seventies: 2 younger unaffected family members also carried the mutation, consistent with either incomplete penetrance or their being younger than disease onset.
REFERENCES
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Bances, P., Fernandez, M.-R., Rodriguez-Garcia, M.-I., Morgan, R. O., Fernandez, M.-P. Annexin A11 (ANXA11) gene structure as the progenitor of paralogous annexins and source of orthologous cDNA isoforms. Genomics 69: 95-103, 2000. [PubMed: 11013079] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0888-7543(00)96309-2]
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Misaki, Y., Pruijn, G. J. M., van der Kemp, A. W. C. M., van Venrooij, W. J. The 56K autoantigen is identical to human annexin XI. J. Biol. Chem. 269: 4240-4246, 1994. [PubMed: 7508441] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=7508441]
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Morgan, R. O., Bell, D. W., Testa, J. R., Fernandez, M. P. Genomic locations of ANX11 and ANX13 and the evolutionary genetics of human annexins. Genomics 48: 100-110, 1998. [PubMed: 9503022] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0888-7543(97)95148-X]
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Smith, B. N., Topp, S. D., Fallini, C., Shibata, H., Chen, H.-J., Troakes, C., King, A., Ticozzi, N., Kenna, K. P., Soragia-Gkazi, A., Miller, J. W., Sato, A., and 44 others. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Sci. Transl. Med. 9: eaad9157, 2017. Note: Electronic Article. [PubMed: 28469040] [Full Text: http://stm.sciencemag.org/cgi/pmidlookup?view=short&pmid=28469040]
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