Alternative titles; symbols
HGNC Approved Gene Symbol: MAGED2
Cytogenetic location: Xp11.21 Genomic coordinates (GRCh38) : X:54,807,745-54,816,015 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.21 | Bartter syndrome, type 5, antenatal, transient | 300971 | X-linked recessive | 3 |
By database searching with the sequence of MAGEA10 (300343) as query, Lucas et al. (1999) identified a distantly related but homologous gene, MAGED2, which they designated MAGED. The deduced 606-amino acid protein contains a segment in its central region that is homologous to the 200-amino acid MAGE segment at the C terminus of other MAGE proteins. RT-PCR analysis demonstrated that, unlike the testis- and tumor-specific expression of many MAGE genes, MAGED2 is expressed ubiquitously in normal human tissues and in most, if not all, cell types. Sequence analysis of MAGED2 and necdin (602117) did not reveal any of the known MAGE antigenic peptides.
Langnaese et al. (2001) also cloned human MAGED2 as well as the rat and mouse orthologs. The human protein contains several putative nuclear localization signals and potential phosphorylation sites for protein kinases. It shares 86% and 43% overall sequence identity with the rat ortholog and human MAGED1 (300224), respectively. Northern blot analysis detected a 2.2-kb transcript in human brain, skeletal muscle, heart, placenta, and pancreas, and in lower amounts in kidney and lung. Expression was detectable in several human brain regions. In situ hybridization in rat brain showed marked expression in hippocampus, cerebellum, choroid plexus, and in various nuclei of the hypothalamus and brainstem. In rat testis, MAGED2 was detected only in the interstitium, most probably in the Leydig cells, whereas no expression was detected in the tubuli.
Lucas et al. (1999) determined that the MAGED2 gene contains 14 exons, of which 2 are alternative first exons. The ORF begins in exon 2 and ends in exon 12. Langnaese et al. (2001) stated that the gene spans approximately 8.3 kb.
By genomic sequence analysis, Lucas et al. (1999) identified the MAGED2 gene in a PAC clone mapped by FISH to Xp11. Langnaese et al. (2001) identified the MAGED2 gene with the Xp11.2 hotspot for X-linked mental retardation (XLMR).
See 300016 for a discussion of the high frequency of genes on the X chromosome encoding proteins with the MAGE domain as well as other cancer-testis antigen genes (Ross et al., 2005).
Langnaese et al. (2001) identified 5 SNPs encoding synonymous amino acids in the protein sequence of MAGED2 in patients with XLMR.
In 9 families with transient antenatal Bartter syndrome (BARTS5; 300971), in which mothers of affected male fetuses develop early-onset severe polyhydramnios, Laghmani et al. (2016) identified mutations in the MAGED2 gene (see, e.g., 300470.0001-300470.0004). The fetal genotype was demonstrated to be both necessary and sufficient for the full obstetric and perinatal phenotype by a de novo mutation (K133X; 300470.0005) detected in the affected male infant in 1 family.
In a family with transient antenatal Bartter syndrome type 5 (BARTS5; 300971), Laghmani et al. (2016) identified a c.1038C-G transversion in exon 7 of the MAGED2 gene, resulting in a tyr346-to-ter (Y346X) substitution. The mutation cosegregated with the 3 affected males and both carrier mothers, and was not found in 110 controls or in the 1000 Genomes or ExAC databases.
In a German family with transient antenatal Bartter syndrome type 5 (BARTS5; 300971), originally reported by Engels et al. (1991), Laghmani et al. (2016) identified a splice site transition (c.991-2A-G) in intron 6 of the MAGED2 gene. The mutation, which was not found in 110 controls or in the 1000 Genomes or ExAC databases, was present in the carrier mother and all 3 affected sons, the eldest of whom had polyhydramnios only and did not exhibit polyuria postnatally.
In a Flemish family with transient antenatal Bartter syndrome type 5 (BARTS5; 300971), originally reported by Reinalter et al. (1998), Laghmani et al. (2016) identified a 2-bp deletion (c.386delTG) in exon 3 of the MAGED2 gene, causing a frameshift predicted to result in a premature termination codon (Val129GlyfsTer2). The mutation was present in the mother and her affected son, but was not found in 110 controls or in the 1000 Genomes or ExAC databases. An earlier pregnancy had also been complicated by polyhydramnios, with premature delivery at 25 weeks' gestation of a male infant who died at 7 hours of life.
In a woman with early-onset severe polyhydramnios and her male fetus who died at 22 weeks' gestation (BARTS5; 300971), Laghmani et al. (2016) identified a c.1336C-T transition in exon 11 of the MAGED2 gene, resulting in an arg446-to-cys (R446C) substitution. The mutation was not found in 110 controls or in the 1000 Genomes or ExAC databases.
In a male infant with transient antenatal Bartter syndrome-5 (BARTS5; 300971), Laghmani et al. (2016) identified a de novo c.397A-T transversion in exon 3 of the MAGED2 gene, resulting in a lys133-to-ter (K133X) substitution. The mutation was not found in 110 controls or in the 1000 Genomes or ExAC databases; it also was not detected in the proband's mother, who experienced early-onset severe polyhydramnios, thus demonstrating that the fetal genotype is sufficient for the full obstetric and perinatal phenotype.
Engels, A., Gordjani, N., Nolte, S., Seyberth, H. W. Angeborene passagere hyperprostaglandinurische Tubulopathie bei zwei fruhgeborenen Geschwistern. Mschr. Kinderheilk. 139: 185 only, 1991.
Laghmani, K., Beck, B. B., Yang, S.-S., Seaayfan, E., Wenzel, A., Reusch, B., Vitzthum, H., Priem, D., Demaretz, S., Bergmann, K., Duin, L. K., Gobel, H., and 21 others. Polyhydramnios, transient antenatal Bartter's syndrome, and MAGED2 mutations. New Eng. J. Med. 374: 1853-1863, 2016. [PubMed: 27120771] [Full Text: https://doi.org/10.1056/NEJMoa1507629]
Langnaese, K., Kloos, D. U., Wehnert, M., Seidel, B., Wieacker, P. Expression pattern and further characterization of human MAGED2 and identification of rodent orthologues. Cytogenet. Cell Genet. 94: 233-240, 2001. [PubMed: 11856887] [Full Text: https://doi.org/10.1159/000048822]
Lucas, S., Brasseur, F., Boon, T. A new MAGE gene with ubiquitous expression does not code for known MAGE antigens recognized by T cells. Cancer Res. 59: 4100-4103, 1999. [PubMed: 10463614]
Reinalter, S., Devlieger, H., Proesmans, W. Neonatal Bartter syndrome: spontaneous resolution of all signs and symptoms. Pediat. Nephrol. 12: 186-188, 1998. [PubMed: 9630034] [Full Text: https://doi.org/10.1007/s004670050433]
Ross, M. T., Grafham, D. V., Coffey, A. J., Scherer, S., McLay, K., Muzny, D., Platzer, M., Howell, G. R., Burrows, C., Bird, C. P., Frankish, A., Lovell, F. L., and 270 others. The DNA sequence of the human X chromosome. Nature 434: 325-337, 2005. [PubMed: 15772651] [Full Text: https://doi.org/10.1038/nature03440]