Alternative titles; symbols
HGNC Approved Gene Symbol: ANO5
SNOMEDCT: 715568002, 726616006, 783166000; ICD10CM: G71.035;
Cytogenetic location: 11p14.3 Genomic coordinates (GRCh38) : 11:22,192,473-22,283,357 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p14.3 | Gnathodiaphyseal dysplasia | 166260 | Autosomal dominant | 3 |
| Miyoshi muscular dystrophy 3 | 613319 | Autosomal recessive | 3 | |
| Muscular dystrophy, limb-girdle, autosomal recessive 12 | 611307 | Autosomal recessive | 3 |
ANO5 is a member of the anoctamin family of calcium-activated chloride channels (summary by Marconi et al., 2013).
By searching databases for sequences similar to TMEM16A (ANO1; 610108), Katoh and Katoh (2004) identified TMEM16E (ANO5). The deduced 913-amino acid protein contains 8 transmembrane domains. The N and C termini are cytoplasmic, and the extracellular regions contain 6 putative N-glycosylation sites. Katoh and Katoh (2004) also identified a splice variant lacking exon 4. TMEM16E and TMEM16F (ANO6; 608663) share 50.3% amino acid identity. By EST database analysis, Katoh and Katoh (2004) determined that TMEM16E is expressed in testis and pancreatic islet.
In a search for candidate genes for gnathodiaphyseal dysplasia (GDD; 166260), Tsutsumi et al. (2004) identified a novel gene (ANO5), which they named GDD1, within the GDD critical region on 11p15.1-p14.3.
Katoh and Katoh (2004) determined that the TMEM16E gene contains 22 exons and spans more than 88.8 kb.
Tsutsumi et al. (2004) determined that the TMEM16E gene spans approximately 90 kb of genomic DNA. The initiation and stop codons (ATG and TAA) are present in exons 1 and 22, respectively.
Mizuta et al. (2007) studied the molecular and biochemical functions of GDD1 protein. They examined the murine GDD1 gene expression pattern during embryonic development, and characterized the cellular and tissue localizations of its gene product using a GDD1-specific antibody. In the developing embryos, GDD1 mRNA expression was principally associated with differentiating and developing somites, with a highly complex spatiotemporal pattern that involved the myotomal and sclerotomal lineages of somites. Biochemical studies indicated that GDD1 protein is an integral membrane glycoprotein that resides predominantly in intracellular vesicles. Immunohistochemical analysis showed a high level of murine GDD1 protein expression in cardiac and skeletal muscle tissues, and in growth-plate chondrocytes and osteoblasts in bone. The observations suggested that the GDD1 protein has diverse cellular role(s) in the development of the musculoskeletal system.
In contrast to cells transfected with ANO1, Marconi et al. (2013) found that transfection of ANO5 into HEK293 cells did not result in calcium-activated anionic transport, suggesting that ANO5 does not act as a plasma membrane calcium-activated chloride channel.
By genomic sequence analysis, Katoh and Katoh (2004) mapped the TMEM16E gene to chromosome 11p14.3, where it is linked to the NELL1 gene (602319) at chromosome 11p15.1. This locus is paralogous to the NELL2 (602320)-TMEM16F locus on chromosome 12q12. Katoh and Katoh (2004) also mapped the mouse Tmem16e gene to chromosome 7B3.
Gnathodiaphyseal Dysplasia
Tsutsumi et al. (2004) identified heterozygous mutations in the GDD1 gene in patients from 2 families with gnathodiaphyseal dysplasia (GDD; 166260): C356R (608662.0001) in the original Japanese family reported by Akasaka et al. (1969) and C356G (608662.0002) in an African American family. The cysteine residue at amino acid 356 is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggested a role for the gene product in the regulation of intracellular calcium homeostasis.
Marconi et al. (2013) identified a heterozygous missense mutation in the ANO5 gene (608662.0009) in affected members of an Italian family with gnathodiaphyseal dysplasia. The mutation segregated with the disorder in the family and was not found in several large control databases. Functional studies were not performed.
Autosomal Recessive Muscular Dystrophies
In affected individuals with autosomal recessive limb-girdle muscular dystrophy-12 (LGMDR12; 611307), previously symbolized LGMD2L, Bolduc et al. (2010) identified homozygous or compound heterozygous mutations in the ANO5 gene (608662.0003-608662.0005). The phenotype was characterized by late-onset proximal scapular and pelvic girdle muscle weakness and asymmetrical muscle atrophy. Bolduc et al. (2010) identified a homozygous mutation in the ANO5 gene (608662.0006) in 2 Finnish brothers with late-onset distal Miyoshi muscular dystrophy-3 (MMD3; 613319). One woman with a phenotype overlapping that of LGMD2L and MMD3 was compound heterozygous for 2 mutations (608662.0004-608662.0005). The findings indicated that these 2 disorders are allelic.
Penttila et al. (2012) found 11 different recessive mutations in the ANO5 gene in 25 (about 25%) of 101 patients with undiagnosed distal calf myopathy or LGMD. Eighteen patients were Finnish, 2 were Spanish, 3 were American of German descent, 1 was Australian, and 1 was Italian. The most common mutation was R758C (608662.0006), homozygous in 9 Finnish patients and heterozygous in 11 patients, followed by 191dupA (608662.0004), which was found in 10 patients. Other mutations (see, e.g., 608662.0007-608662.0008) were private. Although all patients had increased serum creatine kinase, part of the inclusion criteria, the phenotype was variable and there were no genotype/phenotype correlations. Most males had proximal muscle weakness affecting the lower and/or upper limbs, most consistent with LGMD2L, whereas females had milder symptoms such as myalgias, calf hypertrophy, or isolated hyperCKemia in the absence of clinical muscle weakness.
In the Japanese family in which gnathodiaphyseal dysplasia (GDD; 166260) was first described by Akasaka et al. (1969), Tsutsumi et al. (2004) identified heterozygosity for a cys356-to-arg (C356R) mutation caused by a T-to-C transition in exon 11 of the GDD1 gene.
In an African American family with gnathodiaphyseal dysplasia (GDD; 166260), Tsutsumi et al. (2004) identified a T-to-G transversion in exon 11 of the GDD1 gene, resulting in a cys356-to-gly (C356G) substitution. A father and son were affected.
In affected members of 2 unrelated French Canadian families with limb-girdle muscular dystrophy type 2L (LGMDR12; 611307), Bolduc et al. (2010) identified a homozygous 1295C-G transversion in exon 13 of the ANO5 gene, which created a putative splice donor site within exon 13. Amplification and sequencing of patient cDNA confirmed the aberrant splicing of exon 13, resulting in a frameshift and premature termination consistent with a loss of function. One of the families was known to be consanguineous and had been reported by Jarry et al. (2007). Haplotype analysis suggested a founder effect. The mutation was not found in 210 French Canadian or 162 CEPH control chromosomes.
Bolduc et al. (2010) found homozygosity for a 1-bp duplication (191dupA) in exon 5 of the ANO5 gene in a Dutch family with Miyoshi muscular dystrophy-3 (MMD3; 613319) originally reported by Linssen et al. (1998) as family IV. The 191dupA mutation resulted in a frameshift and premature termination, consistent with a loss of function. It was absent in 210 French Canadian and 152 CEPH control chromosomes, but was identified in 1 of 100 UK and 2 of 210 Dutch control chromosomes.
In a 63-year-old French Canadian woman with autosomal recessive limb-girdle muscular dystrophy type 2L (LGMDR12; 611307) and mild distal limb weakness, Bolduc et al. (2010) identified compound heterozygosity for 191dupA and a 692G-T transversion in exon 8 of the ANO5 gene, resulting in a gly231-to-val substitution (G231V; 608662.0005) in the intracellular N-terminal tail. The patient had late-onset asymmetric proximal upper limb and iliopsoas weakness and distal upper and lower limb weakness, as well as increased serum creatine kinase. Bolduc et al. (2010) noted that the phenotype overlapped between LGMD2L and Miyoshi myopathy.
Among 25 patients, mostly of Finnish descent, with variable muscle disorders due to recessive ANO5 mutations, Penttila et al. (2012) found that 191dupA was the second most common mutation, occurring in the heterozygous state with another ANO5 mutation in 10 patients. The phenotype was highly variable: female mutation carriers had a mild disorder with myalgia and/or calf hypertrophy and hyperCKemia, whereas men with the mutation showed distal lower limb weakness or proximal upper and lower limb muscle weakness. The findings indicated that this mutation can be associated with a variety of muscle phenotypes. Two Spanish brothers with LGMD2L were compound heterozygous for 191dupA and G231V.
For discussion of the 692G-T transversion in exon 8 of the ANO5 gene, resulting in a gly231-to-val substitution (G231V) in the intracellular N-terminal tail, that was found in compound heterozygous state in a patient with limb-girdle muscular dystrophy type 2L (LGMDR12; 611307) and mild distal limb weakness by Bolduc et al. (2010), see 608662.0004.
In 2 Finnish brothers with Miyoshi muscular dystrophy-3 (MMD3; 613319), Bolduc et al. (2010) identified a homozygous 2272C-T transition in exon 20 of the ANO5 gene, resulting in an arg758-to-cys (R758C) substitution in a conserved residue in an extracellular loop. The R758C variant was not detected in 100 UK or 208 French Canadian control chromosomes, but was detected in 1 of 368 Finnish control chromosomes, indicating that this variant is present in the Finnish population at a low frequency. The family had originally been reported by Jaiswal et al. (2007).
Among 25 patients, mostly of Finnish descent, with variable muscle disorders due to recessive ANO5 mutations, Penttila et al. (2012) found that R758C was the most common mutation, occurring in homozygous state in 9 Finnish patients and in heterozygous state with another pathogenic allele (see, e.g., 608662.0007 and 608662.0008) in 11 patients. The phenotype was highly variable: 2 females who were homozygous for the mutation had no clinical muscle weakness and only hyperCKemia, whereas other women with the mutation had myalgia and/or calf hypertrophy. Men with the mutation showed distal lower limb weakness or proximal upper and lower limb muscle weakness (LGMDR12; 611307). The findings indicated that this mutation can be associated with a variety of muscle phenotypes.
In a Finnish man with autosomal recessive limb-girdle muscular dystrophy type 2L (LGMDR12; 611307), Penttila et al. (2012) identified compound heterozygosity for 2 mutations in the ANO5 gene: a G-to-A transition in intron 14 (1407+5G-A), demonstrated to result in the skipping of exon 14, and 191dupA (608662.0004). A Finnish woman with a much milder phenotype had the splice site mutation and R758C (608662.0006). She had myalgia, calf hypertrophy, and increased serum creatine kinase, more consistent with a mild form of Miyoshi myopathy-3 (MMD3; 613319).
In a man with autosomal recessive limb-girdle muscular dystrophy type 2L (LGMDR12; 611307), Penttila et al. (2012) identified compound heterozygosity for 2 mutations in the ANO5 gene: a 2-bp deletion in exon 20 (2311delCA), resulting in a frameshift and premature termination (Gln771AlafsTer8) and R758C (608662.0006).
In affected members of an Italian family with gnathodiaphyseal dysplasia (166260), Marconi et al. (2013) identified a heterozygous c.1538C-T transition in exon 15 of the ANO5 gene, resulting in a thr513-to-ile (T513I) substitution in the second residue of the predicted fourth transmembrane domain. The residue is conserved in many, but not all, mammalian species. The mutation segregated with the disorder in the family and was not found in several large control databases. Functional studies were not performed.
Akasaka, Y., Nakajima, T., Koyama, K., Furuya, K., Mitsuka, Y. Familial cases of new systemic bone disease, hereditary gnatho-diaphyseal sclerosis. Nippon Seikeigeka Gakkai Zasshi 43: 381-394, 1969. [PubMed: 5816667]
Bolduc, V., Marlow, G., Boycott, K. M., Saleki, K., Inoue, H., Kroon, J., Itakura, M., Robitaille, Y., Parent, L., Baas, F., Mizuta, K., Kamata, N., Richard, I., Linssen, W. H. J. P., Mahjneh, I., de Visser, M., Bashir, R., Brais, B. Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am. J. Hum. Genet. 86: 213-221, 2010. [PubMed: 20096397] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.013]
Jaiswal, J. K., Marlow, G., Summerill, G., Mahjneh, I., Mueller, S., Hill, M., Miyake, K., Haase, H., Anderson, L. V. B., Richard, I., Kiuru-Enari, S., McNeil, P. L., Simon, S. M., Bashir, R. Patients with a non-dysferlin Miyoshi myopathy have a novel membrane repair defect. Traffic 8: 77-88, 2007. [PubMed: 17132147] [Full Text: https://doi.org/10.1111/j.1600-0854.2006.00505.x]
Jarry, J., Rioux, M. F., Bolduc, V., Robitaille, Y., Khoury, V., Thiffault, I., Tetreault, M., Loisel, L., Bouchard, J. P., Brais, B. A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13-p12. Brain 130: 368-380, 2007. [PubMed: 17008331] [Full Text: https://doi.org/10.1093/brain/awl270]
Katoh, M., Katoh, M. Identification and characterization of TMEM16E and TMEM16F genes in silico. Int. J. Oncol. 24: 1345-1349, 2004. [PubMed: 15067359]
Linssen, W. H. J. P., de Visser, M., Notermans, N. C., Vreyling, J. P., Van Doorn, P. A., Wokke, J. H. J., Baas, F., Bolhuis, P. A. Genetic heterogeneity in Miyoshi-type distal muscular dystrophy. Neuromusc. Disord. 8: 317-320, 1998. [PubMed: 9673985] [Full Text: https://doi.org/10.1016/s0960-8966(98)00020-0]
Marconi, C., Brunamonti Binello, P., Badiali, G., Caci, E., Cusano, R., Garibaldi, J., Pippucci, T., Merlini, A., Marchetti, C., Rhoden, K. J., Galietta, L. J. V., Lalatta, F., Balbi, P., Seri, M. A novel missense mutation in ANO5/TMEM16E is causative for gnathodiaphyseal dyplasia (sic) in a large Italian pedigree. Europ. J. Hum. Genet. 21: 613-619, 2013. [PubMed: 23047743] [Full Text: https://doi.org/10.1038/ejhg.2012.224]
Mizuta, K., Tsutsumi, S., Inoue, H., Sakamoto, Y., Miyatake, K., Miyawaki, K., Noji, S., Kamata, N., Itakura, M. Molecular characterization of GDD1/TMEM16E, the gene product responsible for autosomal dominant gnathodiaphyseal dysplasia. Biochem. Biophys. Res. Commun. 357: 126-132, 2007. [PubMed: 17418107] [Full Text: https://doi.org/10.1016/j.bbrc.2007.03.108]
Penttila, S., Palmio, J., Suominen, T., Raheem, O., Evila, A., Muelas Gomez, N., Tasca, G., Waddell, L. B., Clarke, N. F., Barboi, A., Hackman, P., Udd, B. Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. Neurology 78: 897-903, 2012. Note: Erratum: Neurology 80: 226 only, 2013. [PubMed: 22402862] [Full Text: https://doi.org/10.1212/WNL.0b013e31824c4682]
Tsutsumi, S., Kamata, N., Vokes, T. J., Maruoka, Y., Nakakuki, K., Enomoto, S., Omura, K., Amagasa, T., Nagayama, M., Saito-Ohara, F., Inazawa, J., Moritani, M., Yamaoka, T., Inoue, H., Itakura, M. The novel gene encoding a putative transmembrane protein is mutated in gnathodiaphyseal dysplasia (GDD). Am. J. Hum. Genet. 74: 1255-1261, 2004. [PubMed: 15124103] [Full Text: https://doi.org/10.1086/421527]