| *608662 | ||||||||||||||||||||||||
| ANOCTAMIN 5; ANO5 | ||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||
| TRANSMEMBRANE PROTEIN 16E; TMEM16E GDD1 GENE; GDD1 | ||||||||||||||||||||||||
| HGNC Approved Gene Symbol: ANO5 | ||||||||||||||||||||||||
| Cytogenetic location: 11p14.3 Genomic coordinates (GRCh37): 11:22,214,721 - 22,304,912 (from NCBI) | ||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||
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| Cloning | ||||||||||||||||||||||||
| By searching databases for sequences similar to TMEM16A (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 (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. | ||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||
| Autosomal Dominant Gnathodiaphyseal Dysplasia Tsutsumi et al. (2004) determined that the GDD1 (ANO5) gene contains the mutations responsible for gnathodiaphyseal dysplasia (GDD; 166260). Heterozygous mutations were identified in 2 families with this autosomal dominant disorder: C356R (608662.0001) in the original Japanese family 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. Autosomal Recessive Muscular Dystrophies In affected individuals with autosomal recessive limb-girdle muscular dystrophy-2L (LGMD2L; 611307), 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. | ||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||
| .0001 GNATHODIAPHYSEAL DYSPLASIA | ||||||||||||||||||||||||
| ANO5, CYS356ARG [dbSNP:rs119103234] | ||||||||||||||||||||||||
| In the Japanese family in which gnathodiaphyseal dysplasia (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 TMEM16E gene. | ||||||||||||||||||||||||
| .0002 GNATHODIAPHYSEAL DYSPLASIA | ||||||||||||||||||||||||
| ANO5, CYS356GLY [dbSNP:rs119103234] | ||||||||||||||||||||||||
| In an African American family with gnathodiaphyseal dysplasia (166260), Tsutsumi et al. (2004) identified a T-to-G transversion in exon 11 of the TMEM16E gene, resulting in a cys356-to-gly (C356G) amino acid change. A father and son were affected. | ||||||||||||||||||||||||
| .0003 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2L | ||||||||||||||||||||||||
| ANO5, 1295C-G | ||||||||||||||||||||||||
| In affected members of 2 unrelated French Canadian families with limb-girdle muscular dystrophy type-2L (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 truncation 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. | ||||||||||||||||||||||||
| .0004 MIYOSHI MUSCULAR DYSTROPHY 3 | ||||||||||||||||||||||||
| MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2L, INCLUDED | ||||||||||||||||||||||||
| ANO5, 1-BP DUP, 191A | ||||||||||||||||||||||||
| 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 (613319) originally reported by Linssen et al. (1998) as family IV. The 191dupA mutation resulted in a frameshift and premature truncation, 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 LGMD2L (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. | ||||||||||||||||||||||||
| .0005 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2L | ||||||||||||||||||||||||
| ANO5, GLY231VAL | ||||||||||||||||||||||||
| See 608662.0004 and Bolduc et al. (2010). | ||||||||||||||||||||||||
| .0006 MIYOSHI MUSCULAR DYSTROPHY 3 | ||||||||||||||||||||||||
| ANO5, ARG758CYS | ||||||||||||||||||||||||
| In 2 Finnish brothers with Miyoshi muscular dystrophy-3 (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). | ||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||
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