HGNC Approved Gene Symbol: EPB42
Cytogenetic location: 15q15.2 Genomic coordinates (GRCh38): 15:43,197,227-43,225,737 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.2 | Spherocytosis, type 5 | 612690 | 3 |
Korsgren et al. (1990) cloned and sequenced protein band 4.2 from a human reticulocyte cDNA library. The deduced 691-amino acid band 4.2 protein has homology with 2 closely related calcium-dependent crosslinking proteins, guinea pig liver transglutaminase and the alpha subunit of human coagulation factor XIII (F13A1; 134570). Within the 5 contiguous consensus residues of the transglutaminase active site, band 4.2 has an amino acid substitution which leads to loss of transglutaminase activity. Sung et al. (1990) also cloned protein 4.2 and likewise found homology to the 2 transglutaminases, as well as the lack of the critical residue required for enzymatic crosslinking of substrates.
Korsgren and Cohen (1991) showed that reticulocytes contain 2 different sized EPB42 messages; the major, smaller, message is produced by alternative splicing. They found that the human and murine proteins share 72% sequence identity.
Korsgren and Cohen (1991) showed that the band 4.2 gene is about 20 kb long and contains 13 exons. Alignment of the band 4.2 amino acid sequence with that of F13A2 and division of the sequences into exons showed a remarkable correspondence, and in most cases identity, in the sizes of the paired exons.
Korsgren and Cohen (1994) found that the organization and size of the human and mouse EPB42 genes are identical.
Sung et al. (1991) mapped the EPB42 gene to 15q15-q21 by fluorescence in situ hybridization. Najfeld et al. (1992) assigned the gene to 15q15 by fluorescence in situ hybridization. White et al. (1992) mapped the Epb42 gene to mouse chromosome 2, which shares an extensive segment of syntenic homology with human chromosome 15.
By long-range genomic PCR, Grenard et al. (2001) mapped the EPB42 gene to a 100-kb region of 15q15.2, arranged in tandem with 2 other transglutaminase genes, TGM5 (603805) and TGM7 (606776). By radiation hybrid analysis, Grenard et al. (2001) mapped the mouse Epb42, Tgm5, and Tgm7 genes in close proximity on chromosome 2.
In the red cell membrane skeleton, protein 4.2 may regulate the association of protein 3 (109270) with ankyrin (612641) (Davies and Lux, 1989).
Azim et al. (1996) demonstrated that both protein 4.2 and dematin (125305) are ATP-binding proteins.
Bruce et al. (2002) observed that protein 4.2 and CD47 interact in the human red cell membrane, which provided further evidence for an association between the band 3 complex (which includes protein 4.2) and the Rh complex, and defined a point of attachment between the Rh complex and the red cell cytoskeleton.
In 4 unrelated Japanese patients with autosomal recessive hereditary spherocytosis (SPH5; 612690), Bouhassira et al. (1991, 1992) identified homozygosity for a mutation in the EPB42 gene (177070.0001).
In a Portuguese woman with recessively transmitted hemolytic anemia, Hayette et al. (1995) identified a mutation in the EPB42 gene (177070.0002).
In Tunisian sibs with autosomal recessive hemolytic anemia reported by Ghanem et al. (1990), Hayette et al. (1995) identified homozygosity for a mutation in the EPB42 gene (177070.0003).
The mouse 'pallid' mutation (see 604310) produces defects in at least 3 subcellular organelles: platelet-dense granules, melanosomes, and kidney lysosomes. White et al. (1992) noted that the mouse Epb42 gene mapped to the same region as the pallid mutation in the mouse. Prompted to examine the Epb42 gene in the pallid mouse, they found changes on Southern blot analysis suggesting a mutation; Northern blot analysis demonstrated smaller than normal Epb42 transcripts in affected pallid tissues, such as kidney and skin. However, Gwynn et al. (1997) and White et al. (1997) excluded Epb42 as a candidate for the mouse pallid mutation. On Northern blot analysis of normal and pallid mouse kidney, Gwynn et al. (1997) observed that the truncated Epb42 protein comigrated with normal Epb42 protein. As the pallid mutation originally arose in a wild M. domesticus mouse, they concluded that the Epb42 protein characteristic of pallid is a normal polymorphism and that Epb42 and pallid are distinct loci.
In 4 unrelated Japanese patients with spherocytosis (SPH5; 612690), Bouhassira et al. (1991, 1992) identified homozygosity for a G-to-A transition in the EPB42 gene, resulting in an ala142-to-thr (A142T) substitution. The abnormality in protein 4.2 results in abnormally shaped and osmotically fragile RBCs. The mutation occurred in an alternatively spliced exon that is present in 2 of 4 EPB42 mRNA splicing isoforms. Thus this is a recessive form of spherocytosis causing hereditary hemolytic anemia.
Iwamoto et al. (1993) identified the same mutation in a 27-year-old Japanese female with acute hemolytic crisis and in her sister.
Perrotta et al. (1999) described the 4.2-Nippon mutation in a 30-year-old female born in a small mountain village in central Italy. There was no Japanese ancestry. Splenomegaly and moderate hemolytic anemia were present from birth.
Hayette et al. (1995) identified a defect in the EPB42 gene in a 26-year-old Portuguese woman with recessively transmitted hereditary hemolytic anemia (SPH5; 612690). Protein 4.2 was absent from red cell ghosts by Western blotting. Nucleotide sequencing disclosed deletion of a single nucleotide at position 264 (or 265): AAG GTG was changed to AAG TG in codon 88 (or 89) in exon 2. This change, defining allele 4.2 Lisboa, placed in frame the nonsense TGA triplet that normally overlaps codons 136 and 137 (GTG ACC). In effect, codon 89 was changed from GTG (val) to TGA (stop). The mutation was present in homozygous state in the proband and in heterozygous state in the parents and a brother. Apart from anemia, the patient was free of clinical manifestations. Hayette et al. (1995) noted that in this case there were only a few spherocytes and only a limited decrease in the osmotic resistance.
Using high-sensitivity Western blot analysis, Hayette et al. (1995) found that the Tunisian sibs with autosomal recessive hemolytic anemia (SPH5; 612690) originally reported by Ghanem et al. (1990) had trace amounts of the EPB42 protein. They found that the sibs were homozygous for a G-to-A transition in exon 7 of the EPB42 gene, resulting in an arg310-to-gln (R310Q) substitution. The parents were heterozygous for the mutation, which was absent in 48 control chromosomes of Tunisian individuals.
Protein 4.2 (Notame) was found in a 56-year-old Japanese man being investigated for chronic hyperbilirubinemia (Matsuda et al., 1995). He had mild splenomegaly and mild anemia with reticulocytosis as well as microspherocytosis (SPH5; 612690). Erythrocyte osmotic fragility was remarkably increased. SDS-PAGE showed complete deficiency of protein 4.2. Direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes indicated that the man was a compound heterozygote for the A142T mutation (177070.0001) and a single nucleotide substitution (G to A) in the first nucleotide of intron 6 of the EPB42 gene. RT-PCR analysis using total RNA isolated from reticulocytes of the proband showed that the intron 6 donor site mutation caused exon 6 to be spliced out with intron 6. The abnormal mRNA had a premature termination codon as a result of a frameshift, which precipitated instability of the protein that led to its degradation.
Bruce et al. (2002) presented data on a patient of Pakistani origin with recessive spherocytosis due to absence of protein 4.2 (SPH5; 612690). EPB42 cDNA sequence analysis showed the presence of a 41-bp frameshift deletion in the 5-prime end of exon 11 of the EPB42 gene that produced a truncated peptide designated protein 4.2 Hammersmith. Quantitative RT-PCR indicated that the mutant mRNA was unstable. Sequencing of genomic DNA showed that the deletion stemmed from aberrant splicing. The proband was homozygous for a G-to-T substitution at position 1747 that activated a cryptic acceptor splice site within exon 11 of the EPB42 gene. The proband's mother was heterozygous for this substitution. Unlike protein 4.2-null mice, the proband's red cells showed no evidence of abnormal cation permeability. Quantitation of red cell membrane proteins showed that CD47 (601028) was markedly reduced to about 1% (in the proband) and 65% (in the mother) of that found in healthy controls.
Azim, A. C., Marfatia, S. M., Korsgren, C., Dotimas, E., Cohen, C. M., Chishti, A. H. Human erythrocyte dematin and protein 4.2 (pallidin) are ATP binding proteins. Biochemistry 35: 3001-3006, 1996. [PubMed: 8608138] [Full Text: https://doi.org/10.1021/bi951745y]
Bouhassira, E. E., Schwartz, R. S., Yawata, Y., Ata, K., Kanzaki, A., Qui, J. J.-H., Nagel, R. L., Rybicki, A. C. An alanine-to-threonine substitution in protein 4.2 cDNA is associated with a Japanese form of hereditary hemolytic anemia (protein 4.2-Nippon). Blood 79: 1846-1854, 1992. [PubMed: 1558976]
Bouhassira, E. E., Schwartz, R. S., Yawata, Y., Ata, K., Nagel, R. L., Rybicki, A. C. An alanine to threonine substitution in protein 4.2 cDNA is associated with a Japanese form of hereditary hemolytic anemia. (Abstract) Clin. Res. 39: 313A, 1991.
Bruce, L. J., Ghosh, S., King, M. J., Layton, D. M., Mawby, W. J., Stewart, G. W., Oldenborg, P.-A., Delaunay, J., Tanner, M. J. A. Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex. Blood 100: 1878-1885, 2002. [PubMed: 12176912] [Full Text: https://doi.org/10.1182/blood-2002-03-0706]
Davies, K. A., Lux, S. E. Hereditary disorders of the red cell membrane skeleton. Trends Genet. 5: 222-227, 1989. [PubMed: 2675425] [Full Text: https://doi.org/10.1016/0168-9525(89)90086-3]
Ghanem, A., Pothier, B., Marechal, J., Ducluzeau, M. T., Morle, L., Alloisio, N., Feo, C., Ben Abdeladhim, A., Fattoum, S., Delaunay, J. A haemolytic syndrome associated with the complete absence of red cell membrane protein 4.2 in two Tunisian siblings. Brit. J. Haemat. 75: 414-420, 1990. [PubMed: 2386772] [Full Text: https://doi.org/10.1111/j.1365-2141.1990.tb04357.x]
Grenard, P., Bates, M. K., Aeschlimann, D. Evolution of transglutaminase genes: identification of a transglutaminase gene cluster on human chromosome 15q15: structure of the gene encoding transglutaminase X and a novel gene family member, transglutaminase Z. J. Biol. Chem. 276: 33066-33078, 2001. [PubMed: 11390390] [Full Text: https://doi.org/10.1074/jbc.M102553200]
Gwynn, B., Korsgren, C., Cohen, C. M., Ciciotte, S. L., Peters, L. L. The gene encoding protein 4.2 is distinct from the mouse platelet storage pool deficiency mutation pallid. Genomics 42: 532-535, 1997. [PubMed: 9205130] [Full Text: https://doi.org/10.1006/geno.1997.4764]
Hayette, S., Dhermy, D., dos Santos, M.-E., Bozon, M., Drenckhahn, D., Alloisio, N., Texier, P., Delaunay, J., Morle, L. A deletional frameshift mutation in protein 4.2 gene (allele 4.2 Lisboa) associated with hereditary hemolytic anemia. Blood 85: 250-256, 1995. [PubMed: 7803799]
Hayette, S., Morle, L., Bozon, M., Ghanem, A., Risinger, M., Korsgren, C., Tanner, M. J. A., Fattoum, S., Cohen, C. M., Delaunay, J. A point mutation in the protein 4.2 gene (allele 4.2 Tozeur) associated with hereditary haemolytic anaemia. Brit. J. Haemat. 89: 762-770, 1995. [PubMed: 7772513] [Full Text: https://doi.org/10.1111/j.1365-2141.1995.tb08413.x]
Iwamoto, S., Kajii, E., Omi, T., Kamesaki, T., Akifuji, Y., Ikemoto, S. Point mutation in the band 4.2 gene associated with autosomal recessively inherited erythrocyte band 4.2 deficiency. Europ. J. Haemat. 50: 286-291, 1993. [PubMed: 8319790] [Full Text: https://doi.org/10.1111/j.1600-0609.1993.tb00164.x]
Korsgren, C., Cohen, C. M. Organization of the gene for human erythrocyte membrane protein 4.2: structural similarities with the gene for the A subunit of factor XIII. Proc. Nat. Acad. Sci. 88: 4840-4844, 1991. [PubMed: 2052563] [Full Text: https://doi.org/10.1073/pnas.88.11.4840]
Korsgren, C., Cohen, C. M. cDNA sequence, gene sequence, and properties of murine pallidin (band 4.2), the protein implicated in the murine pallid mutation. Genomics 21: 478-485, 1994. [PubMed: 7959722] [Full Text: https://doi.org/10.1006/geno.1994.1304]
Korsgren, C., Lawler, J., Lambert, S., Speicher, D., Cohen, C. M. Complete amino acid sequence and homologies of human erythrocyte membrane protein band 4.2. Proc. Nat. Acad. Sci. 87: 613-617, 1990. [PubMed: 2300550] [Full Text: https://doi.org/10.1073/pnas.87.2.613]
Matsuda, M., Hatano, N., Ideguchi, H., Takahira, H., Fukumaki, Y. A novel mutation causing an aberrant splicing in the protein 4.2 gene associated with hereditary spherocytosis (protein 4.2-Notame). Hum. Molec. Genet. 4: 1187-1191, 1995. [PubMed: 8528207] [Full Text: https://doi.org/10.1093/hmg/4.7.1187]
Najfeld, V., Ballard, S. G., Menninger, J., Ward, D. C., Bouhassira, E. E., Schwartz, R. S., Nagel, R. L., Rybicki, A. C. The gene for human erythrocyte protein 4.2 maps to chromosome 15q15. Am. J. Hum. Genet. 50: 71-75, 1992. [PubMed: 1729896]
Perrotta, S., Iolascon, A., Polito, R., d'Urzo, G., Conte, M. L., Miraglia del Giudice, E. 4.2 Nippon mutation in a non-Japanese patient with hereditary spherocytosis. (Letter) Haematologica 84: 660-662, 1999. [PubMed: 10406914]
Sung, L. A., Chien, S., Chang, L.-S., Lambert, K., Bliss, S. A., Bouhassira, E. E., Nagel, R. L., Schwartz, R. S., Rybicki, A. C. Molecular cloning of human protein 4.2: a major component of the erythrocyte membrane. Proc. Nat. Acad. Sci. 87: 955-959, 1990. [PubMed: 1689063] [Full Text: https://doi.org/10.1073/pnas.87.3.955]
Sung, L. A., Fan, Y. S., Lambert, K., Chien, S., Lin, C. Mapping of gene for human erythrocyte protein 4.2 to chromosomal region 15q15-q21. (Abstract) Cytogenet. Cell Genet. 58: 1996, 1991.
White, R. A., Dowler, L. L., Hummel, G. S., Adkison, L. R. Exclusion of Epb4.2 as a candidate for the mouse mutant pallid. Mouse Genome 95: 492-494, 1997.
White, R. A., Peters, L. L., Adkison, L. R., Korsgren, C., Cohen, C. M., Lux, S. E. The murine pallid mutation is a platelet storage pool disease associated with the protein 4.2 (pallidin) gene. Nature Genet. 2: 80-83, 1992. [PubMed: 1284644] [Full Text: https://doi.org/10.1038/ng0992-80]