Elsevier

Genomics

Volume 84, Issue 4, October 2004, Pages 637-646
Genomics

Differential domain evolution and complex RNA processing in a family of paralogous EPB41 (protein 4.1) genes facilitate expression of diverse tissue-specific isoforms

https://doi.org/10.1016/j.ygeno.2004.06.004Get rights and content

Section snippets

Protein conservation patterns indicate differential evolutionary rates of individual domains

We assembled composite cDNAs for the four EPB41-related genes, each of which encodes proteins with the general domain structure depicted in the top of Fig. 1A. Other genes with similar names (EPB41L4A, EPB41L4B, EPB41L5, and EPB41LO) contain only the FERM domain and represent a different subclass within the protein 4.1 superfamily. Comparison of the deduced amino acid sequences for the EPB41-related proteins revealed an alternating pattern of highly conserved domains interspersed with poorly

Discussion

This report presents a comparative genomics view of the complex EPB41-related (protein 4.1) family and highlights a number of mechanisms by which these genes can encode a highly diverse set of tissue-specific polypeptides. Through the use of alternative first exons and alternative pre-mRNA splicing, the structure and function of these important proteins can be specifically adapted to the needs of each individual cell type. Differential domain evolution may play a particularly important role,

Assembly of composite EPB41-related cDNAs

The composite transcripts used for mapping to the human genome assembly were derived from the relevant Refseq entries, annotated as needed to include additional exons not represented in Refseq.

EPB41 (protein 4.1R). Refseq NM_004437 includes alternative first exon 1A plus most of the coding exons with the exception of exons 14, 15, 17A, 17B, and 19. The sources of other exons are as follows: exons 1B and 1C, [36]; exons 14 and 15, [32]; exon 17A, [33]; exon 17B, [34]; and exon 19 [9].

EPB41L2

Acknowledgments

This work was supported by National Institutes of Health Grants HL45182, DK32094, and DK56355, and by the Director, Office of Biological and Environmental Research, U.S. Department of Energy under Contract DE-AC03-76SF00098.

First page preview

First page preview
Click to open first page preview

References (49)

  • M. Deguillien et al.

    Multiple cis elements regulate an alternative splicing event at 4.1R pre-mRNA during erythroid differentiation

    Blood

    (2001)
  • J.P. Huang et al.

    Genomic structure of the locus encoding protein 4.1: structural basis for complex combinational patterns of tissue-specific alternative RNA splicing

    J. Biol. Chem.

    (1993)
  • F. Baklouti et al.

    Organization of the human protein 4.1 genomic locus: new insights into the tissue-specific alternative splicing of the pre-mRNA

    Genomics

    (1997)
  • P.O. Schischmanoff et al.

    Cell shape-dependent regulation of protein 4.1 alternative pre-mRNA splicing in mammary epithelial cells

    J. Biol. Chem.

    (1997)
  • M. Ramez et al.

    Distinct distribution of specific members of protein 4.1 gene family in the mouse nephron

    Kidney Int.

    (2003)
  • M.K. Parra et al.

    Alternative 5′ exons and differential splicing regulate expression of protein 4.1R isoforms with distinct N-termini

    Blood

    (2003)
  • H. Yamakawa et al.

    Molecular characterization of a new member of the protein 4.1 family (brain 4.1) in rat brain

    Brain Res. Mol. Brain Res.

    (1999)
  • J.G. Conboy et al.

    Tissue- and development-specific alternative RNA splicing regulates expression of multiple isoforms of erythroid membrane protein 4.1

    J. Biol. Chem.

    (1991)
  • P. Gascard et al.

    Characterization of multiple isoforms of protein 4.1R expressed during erythroid terminal differentiation

    Blood

    (1998)
  • P. Cramer et al.

    Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer

    Mol. Cell

    (1999)
  • G. Nogues et al.

    Transcriptional activators differ in their abilities to control alternative splicing

    J. Biol. Chem.

    (2002)
  • F. Pagani et al.

    Promoter architecture modulates CFTR exon 9 skipping

    J. Biol. Chem.

    (2003)
  • L.D. Walensky et al.

    The 13-kD FK506 binding protein, FKBP13, interacts with a novel homologue of the erythrocyte membrane cytoskeletal protein 4.1

    J. Cell Biol.

    (1998)
  • Y. Takakuwa et al.

    Restoration of normal membrane stability to unstable protein 4.1-deficient membranes by incorporation of purified protein 4.1

    J. Clin. Invest.

    (1986)
  • Cited by (30)

    • Kernel variable selection for multicategory support vector machines

      2021, Journal of Multivariate Analysis
      Citation Excerpt :

      Moreover, ZNF521 is consistently overexpressed in AML with mixed lineage leukemia [12]. A deficiency of EPB41 (214530_x_at) causes manifestation of red blood cells with abnormal morphology and unstable membranes [33], and altered erythrocyte membrane properties are associated with the childhood ALL patient [13]. In particular, LCK (204890_s_at) has been reported highly expressed in T-cells and to play a key role in the proliferation and survival of prednisone poor responders T-ALL cells, which are often displayed in pediatric T-ALL patients [39].

    • A 130-kDa protein 4.1B regulates cell adhesion, spreading, and migration of mouse embryo fibroblasts by influencing actin cytoskeleton organization

      2014, Journal of Biological Chemistry
      Citation Excerpt :

      The protein 4.1 family has four members (4.1R, 4.1B, 4.1G, and 4.1N) that are encoded by four paralogous genes (4). One common feature of this family is that their mRNAs all undergo extensive alternative splicing, leading to generation of multiple isoforms (5). It has long been assumed that different isoforms possesses diverse functions (5), but functional evidence is limited as yet.

    • Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia

      2012, American Journal of Human Genetics
      Citation Excerpt :

      Other genes of interest with case-only variants include EPB41L1 (MIM 602879), SLC1A2 (MIM 600300), STX4 (MIM 186591), HYDIN (MIM 610812), PCLO (MIM 604918), and ZNF804B. EPB41L1 encodes the erythrocyte membrane protein band 4.1-like N,34 which colocalizes with AMPA receptors at excitatory synapses and is thought to mediate the interaction of the AMPA receptors with the cytoskeleton.35 It has also been shown to be necessary for the formation of calcium waves in the mediation of neurite formation.36

    • Isoforms of protein 4.1 are differentially distributed in heart muscle cells: Relation of 4.1R and 4.1G to components of the Ca<sup>2+</sup> homeostasis system

      2012, Experimental Cell Research
      Citation Excerpt :

      Between the SAB and CTD is a U3 region that is unconserved between each of the four proteins. All of the 4.1 proteins are subject to extensive differential mRNA splicing [21]. In previous work, we detected differentially spliced mRNAs for all four in mouse heart, but only 4.1R, 4.1G and 4.1N mRNA in human heart [22].

    • Genome-wide association study of childhood acute lymphoblastic leukemia in Korea

      2010, Leukemia Research
      Citation Excerpt :

      In our genome-wide association study, 6 novel SNPs in 4 genes in childhood ALL using Affymetrix SNP Array 6.0 platform were associated with childhood ALL (HAO1: rs6140264; EPB41L2: rs9388856, rs9388857, and rs1360756, C2orf3: rs12105972; MAN2A1: rs3776932). Although our observation should be interpreted cautiously due to limited biological plausibility for the observed association between those SNPs and childhood ALL risk, we note that erythrocyte membrane protein band 4.1-like 2 (EPB41L) plays an essential role in determining the structure of the red cell membrane affecting the mechanical properties of the erythrocyte [17–19]. Majumder et al. [20] suggested that alterations in red cell morphology could evoke changes in hemoglobin stability, and that the leukemia associated factors or small molecular weight toxic materials could lead to the formation of membrane pores in the leukemic red cells.

    View all citing articles on Scopus
    View full text