Disease:


  • OMIM ID: 602359 . 602359
  • OMIM diseaseName:
  • OMIM diseaseClinical_Synopsis:
  • OMIM diseaseText: DESCRIPTION The FXYD (pronounced fix-id) gene family, including FXYD1, consists of small membrane proteins containing a core motif of 35 invariant and conserved amino acids centered on a single transmembrane span. The FXYD1 gene encodes phospholemman (PLM), a plasma membrane substrate phosphorylated in response to insulin and adrenergic stimulation (Chen et al., 1997). It is an accessory protein of the Na+, K+/ATPase (Feschenko et al., 2003). CLONING Using RT-PCR with primers based on the published sequence of canine PLM, Chen et al. (1997) cloned the human and rat phospholemman homologs. The predicted 92-amino acid human PLM protein is 94% homologous to that of canine PLM and has a transmembrane domain. Like canine PLM, human PLM induces a hyperpolarization-activated chloride current when expressed in Xenopus oocytes. Northern blot analysis revealed that human PLM is expressed as a 750-bp mRNA in many tissues, with highest expression in skeletal muscle and heart. By EST database searching and in silico analysis, Sweadner and Rael (2000) identified genes and protein sequences for 7 FXYD molecules in rodents and humans. The deduced FXYD1 protein contains 92 amino acids and a signal peptide. Sweadner and Rael (2000) noted that ESTs for FXYD1 are found in nervous system, muscle, reproductive, and transport tissues but not in blood tissues, suggesting wide but not ubiquitous expression. MAPPING By fluorescence in situ hybridization, Chen et al. (1997) mapped the FXYD1 gene to chromosome 19q13.1. GENE FUNCTION In rat brain, Feschenko et al. (2003) showed that phospholemman was highly expressed in the molecular layer of the cerebellum, in Purkinje neurons, and in axons traversing the granule cell layer. Phospholemman was also highly enriched in the choroid plexus, where it colocalized with Na,K-ATPase in the apical membrane. A phospholemman antibody reduced Na,K-ATPase activity in vitro, indicating that phospholemman regulates Na,K-ATPase. By immunohistochemical studies, Deng et al. (2007) demonstrated that Fxyd1 localizes to cell membranes of neurons in mouse frontal cortex; no Fxyd1 staining was seen in astrocytes. Transgenic Mecp2 (300005)-null mice had increased Fxyd1 mRNA and protein levels in the frontal cortex, similar to that observed in patients with Rett syndrome (RTT; 312750), which is caused by mutations in MECP2. Increased Fxyd1 expression in Mecp2-null mice was associated with decreased Na,K-ATPase activity in the frontal cortex. In cultured mouse neurons, overexpression of Fxyd1 was associated with decreased neuronal dendritic tree and spine formation compared to controls, findings that have been observed in Rett syndrome. Finally, chromatin immunoprecipitation assays identified the FXYD1 promoter as an endogenous target of MECP2, which can cause transcriptional regulation of FXYD1, in HEK293T cells transfected with MECP2. Overall, the results suggested that derepression of FXYD1, resulting from inactivation of MECP2, may contribute to the neuropathogenesis of Rett syndrome.
  • OMIM diseaseSee_Also:
  • OMIM diseaseAllelic_Variants:
  • OMIM diseaseCreation_Date: Rebekah S. Rasooly: 2/17/1998
  • OMIM diseaseEdit_History_Data: wwang: 07/14/2010 ckniffin: 7/13/2010 carol: 2/11/2002 carol: 2/1/2002 carol: 5/24/2000 alopez: 4/22/1998 alopez: 4/8/1998 alopez: 2/17/1998
  • OMIM diseaseContributors: Cassandra L. Kniffin - updated: 7/13/2010 Paul J. Converse - updated: 2/11/2002
  • OMIM diseaseReference: 1. Chen, L.-S. K.; Lo, C. F.; Numann, R.; Cuddy, M.: Characterization of the human and rat phospholemman (PLM) cDNAs and localization of the human PLM gene to chromosome 19q13.1. Genomics 41: 435-443, 1997. 2. Deng, V.; Matagne, V.; Banine, F.; Frerking, M.; Ohliger, P.; Budden, S.; Pevsner, J.; Dissen, G. A.; Sherman, L. S.; Ojeda, S. R.: FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Hum. Molec. Genet. 16: 640-650, 2007. 3. Feschenko, M. S.; Donnet, C.; Wetzel, R. K.; Asinovski, N. K.; Jones, L. R.; Sweadner, K. J.: Phospholemman, a single-span membrane protein, is an accessory protein of Na,K-ATPase in cerebellum and choroid plexus. J. Neurosci. 23: 2161-2169, 2003. 4. Sweadner, K. J.; Rael, E.: The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression. Genomics 68: 41-56, 2000.