A nonsense mutation in the erythrocyte band 3 gene associated with decreased mRNA accumulation in a kindred with dominant hereditary spherocytosis.

Jenkins, Patricia B.; Abou‐Alfa, Ghassan K.; Dhermy, Didier; Bursaux, E; Féo, C; Scarpa, Alphonse L.; Lux, Samuel E.; Garbarz, M; Forget, Bernard G.; Pg, Gallagher

doi:10.1172/jci118425

Cited by 39 publications

(21 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This fits with the general observation that concerns genes carrying non-sense and frameshift mutations (for review see Cooper, 1993). It also fits with reports regarding the EPB3 alleles with these types of abnormalities ( Jarolim et al, 1994a;Jenkins et al, 1996;Alloisio et al, 1996).…”

Section: Discussionsupporting

confidence: 88%

“…Several mutations leading to band 3 reduction and HS have been recently identified. They include (i) mutations producing premature termination of translation (at any position along the whole coding sequence) and (ii) substitutions of highly conserved amino acids within the membrane domain, especially in the last membrane spanning segments (TM9-TM14) or at their boundaries (Alloisio et al, 1993(Alloisio et al, , 1996Jarolim et al, 1994aJarolim et al, , b, 1995Bianchi et al, 1995;Maillet et al, 1995;Jenkins et al, 1996;Eber et al, 1996).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Novel band 3 variants (bands 3 Foggia, Napoli I and Napoli II) associated with hereditary spherocytosis and band 3 deficiency: status of the D38A polymorphism within the EPB3 locus

et al. 1997

View full text Add to dashboard Cite

Summary.We report three novel variants of band 3 associated with hereditary spherocytosis: band 3 Foggia (311delC; ACCCAC → ACCAC), band 3 Napoli I (447insT; TCT → TTCT) and band 3 Napoli II (I783N; ATC → AAC). The first two mutations resulted in premature termination of translation, making one haploid set of band 3 mRNA unavailable. Since it affected a highly conserved position at the terminal end of transmembrane domain 11, the third mutation prevented one haploid set of band 3 from becoming incorporated or stabilized into the membrane. These three mutations resulted in a reduction of the band 3 level in the red cell membrane (by 20-25%) and were dominantly transmitted. The D38A substitution (GAC → GCC) is a low frequency change of band 3. In one compound heterozygote D38A/Napoli II, a markedly aggravated picture required early splenectomy. In contrast, the D38A change was not associated with deterioration in another compound heterozygote, carrying in trans, the previously recorded R760W mutation (CGG → TGG). In the aggravated case, SSCP analysis did not exhibit any additional change in the two EPB3 alleles. Nor did it show any alteration in the exons of the two ANK1 alleles, and the aggravating factor remained elusive. The D38A alteration should be regarded as an innocuous polymorphism.Keywords: hereditary spherocytosis, band 3, EPB3 gene, mutations, polymorphism.Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia characterized by spheroidal, osmotically fragile, erythrocytes (for review, see Lux & Palek, 1995). The primary molecular defect can reside in several red cell membrane structural proteins: spectrin, ankyrin, band 3 and protein 4.2. Band 3, or the anion exchanger 1 (AE1), is the most abundant protein of the red cell membrane (1 : 2 × 10 6 monomers per cell) and consists of two domains with distinct functions (for review, see Tanner, 1993). The cytoplasmic domain (residues 1-403) binds a number of proteins including ankyrin and protein 4.2. The membrane domain (residues 404-883) harbours 14 membrane-spanning segments (TM) and mediates chloride-bicarbonate passive antiport. Band 3 cDNA has been entirely sequenced (Tanner et al, 1988;Lux et al, 1989;Schofield et al, 1994), and the structure of the band 3 gene (EPB3) has been determined (Schofield et al, 1994;Sahr et al, 1994). Approximately 20% of HS cases are associated with a substantial reduction of the band 3 amount in the red cell membrane (20-40%). Basically, their inheritance pattern is autosomal dominant and their clinical phenotype is mild to moderate in the heterozygous state. Band 3 deficiency is accompanied by a roughly proportional reduction in protein 4.2. Several mutations leading to band 3 reduction and HS have been recently identified. They include (i) mutations producing premature termination of translation (at any position along the whole coding sequence) and (ii) substitutions of highly conserved amino acids within the membrane domain, especially in the last membrane spanning segments (TM9-TM14) or at their bounda...

show abstract

Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Novel band 3 variants (bands 3 Foggia, Napoli I and Napoli II) associated with hereditary spherocytosis and band 3 deficiency: status of the D38A polymorphism within the EPB3 locus

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Various mutations of the human AE1 (SLC4A1) gene, including missense, nonsense and frameshift mutations, have been reported to cause dominant HS, which is associated with a 20-40% reduction in AE1 protein levels in the red-cell membrane (Jarolim et al, 1994;Jarolim et al, 1996;Alloisio et al, 1996;Alloisio et al, 1997;Dhermy et al, 1997;Jenkins et al, 1996;Tanner, 2002). Total AE1 deficiency in cattle in the homozygous state for a nonsense mutation R664X, corresponding to a premature termination at residue R646 in human AE1, also showed atypical spherocytosis with marked membrane instability (Inaba et al, 1996;Inaba, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies in patients or animals with AE1 mutations failed to demonstrate the presence of mutant AE1 protein in their red-cell membranes. This finding was partly explained, particularly in the case of the nonsense mutations, by the absence of mutant transcripts in the reticulocytes of patients (Jarolim et al, 1996;Jenkins et al, 1996;Dhermy et al, 1997). However, although HS with AE1 deficiency is usually homogeneous with regard to the clinical and biochemical Various mutations in the AE1 (anion exchanger 1, band 3) gene cause dominant hereditary spherocytosis, a common congenital hemolytic anemia associated with deficiencies of AE1 of different degrees and loss of mutant protein from red blood cell membranes.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle

Ito

Koshino

Arashiki

et al. 2006

Journal of Cell Science

View full text Add to dashboard Cite

Various mutations in the AE1 (anion exchanger 1, band 3) gene cause dominant hereditary spherocytosis, a common congenital hemolytic anemia associated with deficiencies of AE1 of different degrees and loss of mutant protein from red blood cell membranes. To determine the mechanisms underlying decreases in AE1 protein levels, we employed K562 and HEK293 cell lines and Xenopus oocytes together with bovine wild-type AE1 and an R664X nonsense mutant responsible for dominant hereditary spherocytosis to analyze protein expression, turnover, and intracellular localization. R664X-mutant protein underwent rapid degradation and caused specifically increased turnover and impaired trafficking to the plasma membrane of the wild-type protein through hetero-oligomer formation in K562 cells. Consistent with those observations, co-expression of mutant and wild-type AE1 reduced anion transport by the wild-type protein in oocytes. Transfection studies in K562 and HEK293 cells revealed that the major pathway mediating degradation of both R664X and wild-type AE1 employed endoplasmic reticulum (ER)-associated degradation through the proteasomal pathway. Proteasomal degradation of R664X protein appeared to be independent of both ubiquitylation and N-glycosylation, and aggresome formation was not observed following proteasome inhibition. These findings indicate that AE1 R664X protein, which is associated with dominant hereditary spherocytosis, has a dominant-negative effect on the expression of wild-type AE1

show abstract

“…Heterogenous mutations have been elucidated (Jarolim et al, 1994a(Jarolim et al, , 1995(Jarolim et al, , 1996Alloisio et al, 1996Alloisio et al, , 1997Jenkins et al, 1996;Maillet et al, 1995;Bianchi et al, 1995;Miraglia del Guidice et al, 1997;Eber et al, 1996). As a consequence, protein 4.2 is diminished at roughly the same proportions as band 3.…”

mentioning

confidence: 99%

Total absence of protein 4.2 and partial deficiency of band 3 in hereditary spherocytosis

et al. 1997

View full text Add to dashboard Cite

Unlike previously reported cases with total protein 4.2 deficiency due to mutations in the EPB42 gene, we describe a total deficiency in protein 4.2 with normal EPB42 alleles. Hereditary spherocytosis (HS) was observed in a Japanese woman (unsplenectomized) and her daughter (splenectomized). The mother showed a partial deficiency in band 3 and a proportional reduction in protein 4.2. She was heterozygous for a novel allele of the EPB3 gene, allele Okinawa, which contains the two mutations that define the Memphis II polymorphism (K56E, AAG → GAG, and P854L, CCG → CTG) and, additionally, the mutation: G714R, GGG → AGG, located in a highly conserved position of transmembrane segment 9. The latter change was responsible for HS. In trans to allele Okinawa, the daughter displayed allele Fukuoka: G130R, GGA → AGA, an allele known to alter the binding of protein 4.2 to band 3. The daughter presented with a more pronounced decrease of band 3, and lacked protein 4.2, resulting in aggravated haemolytic features. Although the father was not available for study, heterozygosity for allele Fukuoka has been documented in another individual who showed no clinical or haematological signs, and a normal content of band 3. We suggest that band 3 Okinawa binds virtually all the protein 4.2 in red cell precursors, band 3 Fukuoka being unable to do so, and that the impossibility of band 3 Okinawa incorporation into the membrane leads to degradation of the band 3 Okinawa protein 4.2 complex. In contrast, band 3 Fukuoka, free of bound protein 4.2, could then incorporate normally into the bilayer. Thus, protein 4.2 would not appear in the daughter's red cell membrane.

show abstract

A nonsense mutation in the erythrocyte band 3 gene associated with decreased mRNA accumulation in a kindred with dominant hereditary spherocytosis.

Abstract: We studied a French kindred with typical hereditary spherocytosis (

Cited by 39 publications

References 53 publications

Novel band 3 variants (bands 3 Foggia, Napoli I and Napoli II) associated with hereditary spherocytosis and band 3 deficiency: status of the D38A polymorphism within the EPB3 locus

Novel band 3 variants (bands 3 Foggia, Napoli I and Napoli II) associated with hereditary spherocytosis and band 3 deficiency: status of the D38A polymorphism within the EPB3 locus

Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle

Total absence of protein 4.2 and partial deficiency of band 3 in hereditary spherocytosis

Contact Info

Product

Resources

About