Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele α<sup>LELY</sup> in erythroid cells

Wilmotte, R; Maréchal, J; Delaunay, Jean

doi:10.1046/j.1365-2141.1999.01271.x

Cited by 13 publications

(9 citation statements)

References 22 publications

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“…11,15 Patients are clinically asymptomatic if they are heterozygote for α LEPRA or α LELY as the chain produced by the normal allele will preferentially dimerize with the beta chain. [15][16][17][18] In contrast, patients have severe hemolytic anemia when α LEPRA or α LELY are paired in trans to a pathogenic SPTA1 allele, as in our patient. This is particularly the case with α LEPRA as it is weak enough to manifest hematological disease whereas α LELY may generate a sufficient supply of α-spectrin.…”

Section: Discussionsupporting

confidence: 48%

Novel mutation in SPTA 1 gene associated with severe hemolytic anemia

Braunreiter¹

2018

JPNC

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Hereditary spherocytosis (HS), elliptocytosis (HE), and pyropoikilocytosis (HPP) are caused by mutations in the genes which encode erythrocyte cytoskeletal proteins. We report a patient with severe hemolytic anemia with a complex set of mutations, including a novel mutation predicted to cause abnormal splicing of SPTA1 gene, highlighting the utility of molecular diagnostics in patients with no identifiable family history of erythrocyte cytoskeletal disorders.

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Section: Discussionsupporting

confidence: 48%

Novel mutation in SPTA 1 gene associated with severe hemolytic anemia

Braunreiter¹

2018

JPNC

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“…A homozygous 1 bp deletion in the polypyrimidine tract preceding exon 4 was also detected in a case of primary SCLC. The polypyrimidine tract is critical for appropriate splicing (Roscigno et al, 1993;Norton, 1994), and mutations in the polypyrimidine tract often cause abnormal splicing (Wilmotte et al, 1999;Magnusson et al, 2000). Therefore, it is possible that the 1 bp deletion also leads to abnormal splicing of the SEZ6L gene.…”

Section: Discussionmentioning

confidence: 99%

Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line

Nishioka

Kohno²,

Takahashi³

et al. 2000

Oncogene

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Frequent allelic losses on chromosome 22q in small cell lung carcinomas (SCLCs) and advanced non-small cell lung carcinomas indicate the presence of tumor suppressor gene(s) on this chromosome arm. We detected a homozygous deletion at 22q12.1 in a SCLC cell line, Lu24. Cloning of the breakpoints of the Lu24 deletion revealed that the deletion was interstitial and 428, 131 bp in size. The deleted region contained the SEZ6L (Seizure 6-like) gene, whose structure had been partially determined by the chromosome 22 sequencing project. We determined the full length cDNA sequence for the SEZ6L gene based on the genomic sequence for the SEZ6L locus using the GENSCAN program and the RT ± PCR method. The deduced SEZ6L protein was a transmembrane protein of 1024 amino acids with multiple domains involved in protein ± protein interaction and signal transduction. SEZ6L expression was detected in a variety of human tissues, including lung, while its expression was detected in 14 (30%) of 46 lung cancer cell lines examined. Missense mutations were detected in three (7%) of the 46 cell lines, and a 1 bp deletion in the polypyrimidine tract preceding exon 4 was detected in one (2%) of 46 primary lung cancers. Therefore, it is possible that genetic and/or epigenetic SEZ6L alterations are involved in the development and/or progression in a subset of lung cancer, although functional analysis of the SEZ6L gene as well as molecular analysis of other genes in the homozygously deleted region is necessary to understand the pathogenetic signi®cance of 22q deletions in human lung carcinogenesis. Oncogene (2000) 19, 6251 ± 6260.

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“…4 The location of the sph 2BC mutation in murine ␣-spectrin is comparable to that of the HE-associated LELY mutations of human ␣-spectrin, a set of 3 linked mutations in exon 40, intron 45, and intron 46. 37,38 The intron 45 mutation of ␣L ELY also produces exon skipping, 37 as do other mutations located farther 5Ј in human ␣-spectrin, including the HE alleles ␣ Dayton , ␣ Oran , and ␣ St. Claude , and the HS allele ␣ Prague . [39][40][41][42] In contrast to the effects of the sph 2BC mutation, the sph J mutation does not eliminate the dimerization site of ␣-spectrin.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the murine erythroid α-spectrin gene alter spectrin mRNA and protein levels and spectrin incorporation into the red blood cell membrane skeleton

Wandersee

Birkenmeier

Bodine

et al. 2003

Blood

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Tetramers of ␣-and ␤-spectrin heterodimers, linked by intermediary proteins to transmembrane proteins, stabilize the red blood cell cytoskeleton. Deficiencies of either ␣-or ␤-spectrin can result in severe hereditary spherocytosis (HS) or hereditary elliptocytosis (HE) in mice and humans. Four mouse mutations, sph, sph Dem , sph 2BC , and sph J , affect the erythroid ␣-spectrin gene, Spna1, on chromosome 1 and cause severe HS and HE. Here we describe the molecular alterations in ␣-spectrin and their consequences in sph 2BC /sph 2BC and sph J /sph J erythrocytes. A splicing mutation, sph 2BC initiates the skipping of exon 41 and premature protein termination before the site required for dimerization of ␣-spectrin with ␤-spectrin. A nonsense mutation in exon 52, sph J eliminates the COOHterminal 13 amino acids. Both defects result in instability of the red cell membrane and loss of membrane surface area. In sph 2BC /sph 2BC , barely perceptible levels of messenger RNA and consequent decreased synthesis of ␣-spectrin protein are primarily responsible for the resultant hemolysis. By contrast, sph J /sph J mice synthesize the truncated ␣-spectrin in which the 13-terminal amino acids are deleted at higher levels than normal, but they cannot retain this mutant protein in the cytoskeleton. The sph J deletion is near the 4.1/actin-binding region at the junctional complex providing new evidence that this 13-amino acid segment at the COOH-terminus of ␣-spectrin is crucial to the stability of the junctional complex. IntroductionMice with mutations in genes encoding membrane skeletal proteins are important models for hereditary spherocytosis (HS). 1 Gene mapping and disrupted protein levels 2,3 identified the affected product and became the basis for the subsequent cloning and sequencing of ␣-spectrin (Spna1), ␤-spectrin (Spnb1), and ankyrin (Ank1) from mouse 4-6 and human DNA. 7-10 ␤-Spectrin is a pivotal protein that provides binding sites for ankyrin, the linker between spectrin and the transmembrane protein band 3; ␣-spectrin heterodimerization; tetramerization of heterodimers 11 ; and 4.1, a protein that joins spectrin tetramers to the transmembrane protein glycophorin C at junctional complexes. 12 Anchoring of the spectrinbased cytoskeleton to the transmembrane proteins band 3 and glycophorin C is essential for red blood cell stability. The nucleotide alterations described for the mouse beta spectrin (ja/ ja), 13 ankyrin (nb/nb), 14 and ␣-spectrin (sph/sph, sph Dem /sph Dem ) 4,15 mutations provide an explanation for the instability of red cells in these mutants and clues to the functional consequences of alterations in specific amino acids. Assessing functional effects of mutations in humans is more difficult because the secondary genetic diversity affects results, mutations are heterogeneous, and clinical severity may vary among patients with the same mutation.The murine ␣-spectrin mutations sph, sph 2BC , and sph J result in severe HS, whereas sph Dem is a unique model for hereditary elliptocytosis (HE). 16 ␣-Spect...

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Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele α^LELY in erythroid cells

Cited by 13 publications

References 22 publications

Novel mutation in SPTA 1 gene associated with severe hemolytic anemia

Novel mutation in SPTA 1 gene associated with severe hemolytic anemia

Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line

Mutations in the murine erythroid α-spectrin gene alter spectrin mRNA and protein levels and spectrin incorporation into the red blood cell membrane skeleton

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Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele αLELY in erythroid cells

Cited by 13 publications

References 22 publications

Novel mutation in SPTA 1 gene associated with severe hemolytic anemia

Novel mutation in SPTA 1 gene associated with severe hemolytic anemia

Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line

Mutations in the murine erythroid α-spectrin gene alter spectrin mRNA and protein levels and spectrin incorporation into the red blood cell membrane skeleton

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Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele α^LELY in erythroid cells