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** '''[[Spectrin]] deficiency:''' The most frequent defect in [[Hereditary spherocytosis|HS]] is [[spectrin]] deficiency. The [[biochemical]] nature and the severity of [[spectrin]] deficiency correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of [[hemolysis]]. [[Spectrin]] deficiency can result from impaired synthesis of spectrin or from [[quantitative]] or [[qualitative]] deficiencies of other proteins that integrate [[spectrin]] into the [[Red blood cell|red cell]] membrane. In the absence of those binding proteins, free spectrin is degraded, leading to [[spectrin]] deficiency. The spectrin protein is a [[tetramer]] made up of alpha-beta dimers. [[Mutation|Mutations]] of alpha-spectrin are associated with [[recessive]] forms of [[Hereditary spherocytosis|HS]], whereas mutations of beta-[[spectrin]] occur in [[autosomal dominant]] forms of HS.<sup> </sup><ref name="PerrottaDella Ragione2009">{{cite journal|last1=Perrotta|first1=S.|last2=Della Ragione|first2=F.|last3=Rossi|first3=F.|last4=Avvisati|first4=R. A.|last5=Di Pinto|first5=D.|last6=De Mieri|first6=G.|last7=Scianguetta|first7=S.|last8=Mancusi|first8=S.|last9=De Falco|first9=L.|last10=Marano|first10=V.|last11=Iolascon|first11=A.|title= -spectrinBari: a truncated -chain responsible for dominant hereditary spherocytosis|journal=Haematologica|volume=94|issue=12|year=2009|pages=1753–1757|issn=0390-6078|doi=10.3324/haematol.2009.010124}}</ref><ref name="pmid19538529">{{cite journal| author=Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B| title=Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. | journal=Br J Haematol | year= 2009 | volume= 146 | issue= 3 | pages= 326-32 | pmid=19538529 | doi=10.1111/j.1365-2141.2009.07759.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19538529 }}</ref> Synthesis of alpha-spectrin is threefold greater than that of beta-spectrin. | ** '''[[Spectrin]] deficiency:''' The most frequent defect in [[Hereditary spherocytosis|HS]] is [[spectrin]] deficiency. The [[biochemical]] nature and the severity of [[spectrin]] deficiency correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of [[hemolysis]]. [[Spectrin]] deficiency can result from impaired synthesis of spectrin or from [[quantitative]] or [[qualitative]] deficiencies of other proteins that integrate [[spectrin]] into the [[Red blood cell|red cell]] membrane. In the absence of those binding proteins, free spectrin is degraded, leading to [[spectrin]] deficiency. The spectrin protein is a [[tetramer]] made up of alpha-beta dimers. [[Mutation|Mutations]] of alpha-spectrin are associated with [[recessive]] forms of [[Hereditary spherocytosis|HS]], whereas mutations of beta-[[spectrin]] occur in [[autosomal dominant]] forms of HS.<sup> </sup><ref name="PerrottaDella Ragione2009">{{cite journal|last1=Perrotta|first1=S.|last2=Della Ragione|first2=F.|last3=Rossi|first3=F.|last4=Avvisati|first4=R. A.|last5=Di Pinto|first5=D.|last6=De Mieri|first6=G.|last7=Scianguetta|first7=S.|last8=Mancusi|first8=S.|last9=De Falco|first9=L.|last10=Marano|first10=V.|last11=Iolascon|first11=A.|title= -spectrinBari: a truncated -chain responsible for dominant hereditary spherocytosis|journal=Haematologica|volume=94|issue=12|year=2009|pages=1753–1757|issn=0390-6078|doi=10.3324/haematol.2009.010124}}</ref><ref name="pmid19538529">{{cite journal| author=Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B| title=Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. | journal=Br J Haematol | year= 2009 | volume= 146 | issue= 3 | pages= 326-32 | pmid=19538529 | doi=10.1111/j.1365-2141.2009.07759.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19538529 }}</ref> Synthesis of alpha-spectrin is threefold greater than that of beta-spectrin. | ||
** The excess alpha chains normally are degraded. [[Heterozygous|Heterozygotes]] for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the [[heterozygous]] state because synthesis of beta-spectrin is the rate-limiting factor. Red cell membranes isolated from individuals with [[autosomal recessive]] [[Hereditary spherocytosis|HS]] have only 40-50% of the normal amount of spectrin (relative to band protein 3). In the [[autosomal dominant]] form of [[Hereditary spherocytosis|HS]], red cell spectrin levels range from 60-80% of normal. Approximately 50% of patients with severe [[recessive]] [[Hereditary spherocytosis|HS]] have a [[point mutation]] at codon (969) that results in an amino acid [[substitution]] ([[alanine]] [Ala]/[[aspartic acid]] [Asp]) at the corresponding site in the alpha-spectrin protein. This leads to a defective binding of spectrin to protein 4.1. [[Mutations]] involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency. Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo [[proteolytic]] degradation. | ** The excess alpha chains normally are degraded. [[Heterozygous|Heterozygotes]] for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the [[heterozygous]] state because synthesis of beta-spectrin is the rate-limiting factor. Red cell membranes isolated from individuals with [[autosomal recessive]] [[Hereditary spherocytosis|HS]] have only 40-50% of the normal amount of spectrin (relative to band protein 3). In the [[autosomal dominant]] form of [[Hereditary spherocytosis|HS]], red cell spectrin levels range from 60-80% of normal. Approximately 50% of patients with severe [[recessive]] [[Hereditary spherocytosis|HS]] have a [[point mutation]] at codon (969) that results in an amino acid [[substitution]] ([[alanine]] [Ala]/[[aspartic acid]] [Asp]) at the corresponding site in the alpha-spectrin protein. This leads to a defective binding of spectrin to protein 4.1. [[Mutations]] involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency. Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo [[proteolytic]] degradation. | ||
** '''Ankyrin defects:''' HS is described in patients with translocation of chromosome 8 or deletion of the short arm of chromosome 8, where the ankyrin gene is located. Patients with HS and deletion of chromosome 8 have a decrease in red cell ankyrin content. Ankyrin is the principal binding site for spectrin on the red cell membrane. Studies of cytoskeletal protein assembly in reticulocytes indicate that ankyrin deficiency leads to decreased incorporation of spectrin. In HS caused by ankyrin deficiency, a proportional decrease in spectrin content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with autosomal dominant HS have combined spectrin and ankyrin deficiency and the two proteins are diminished equally. | ** '''[[Ankyrin]] defects:''' [[Hereditary spherocytosis|HS]] is described in patients with [[Chromosomal translocation|translocation]] of [[Chromosome 8 (human)|chromosome 8]] or [[deletion]] of the [[short arm]] of [[Chromosome 8 (human)|chromosome 8]], where the [[ankyrin]] gene is located. Patients with [[Hereditary spherocytosis|HS]] and [[deletion]] of [[Chromosome 8 (human)|chromosome 8]] have a decrease in [[Red cells|red cell]] [[ankyrin]] content. [[Ankyrin]] is the principal [[binding site]] for [[spectrin]] on the red cell membrane. Studies of [[cytoskeletal protein]] assembly in [[Reticulocyte|reticulocytes]] indicate that [[ankyrin]] deficiency leads to decreased incorporation of [[spectrin]]. In [[Hereditary spherocytosis|HS]] caused by [[ankyrin]] deficiency, a proportional decrease in [[spectrin]] content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with [[autosomal dominant]] HS have combined spectrin and ankyrin deficiency and the two proteins are diminished equally. | ||
** '''Band 3 deficiency:''' Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the erythrocyte membrane. In some individuals with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable. | ** '''Band 3 deficiency:''' Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the erythrocyte membrane. In some individuals with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable. | ||
** '''Protein 4.2 (pallidin) deficiency:''' Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. RBC morphology in these cases is characterized by spherocytes, elliptocytes, or sphero-ovalocytes. Deficiency of protein 4.2 in HS is relatively common in Japan. One mutation that appears to be common in the Japanese population (resulting in protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype. | ** '''Protein 4.2 (pallidin) deficiency:''' Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. RBC morphology in these cases is characterized by spherocytes, elliptocytes, or sphero-ovalocytes. Deficiency of protein 4.2 in HS is relatively common in Japan. One mutation that appears to be common in the Japanese population (resulting in protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype. | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
There is intrinsic defects in erythrocyte membrane proteins that result in RBC cytoskeleton instability. Loss of erythrocyte surface area leads to the spherical shape of RBCs (spherocytes), which are culled rapidly from the circulation by the spleen. Hemolysis mainly confined to the spleen and, therefore, is extravascular. Splenomegaly commonly develops.
Pathophysiology
- The following four abnormalities in RBC membrane proteins have been identified in HS:
- Spectrin deficiency alone
- Combined spectrin and ankyrin deficiency
- Band 3 deficiency
- Protein 4.2 defects
- Spectrin deficiency: The most frequent defect in HS is spectrin deficiency. The biochemical nature and the severity of spectrin deficiency correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of hemolysis. Spectrin deficiency can result from impaired synthesis of spectrin or from quantitative or qualitative deficiencies of other proteins that integrate spectrin into the red cell membrane. In the absence of those binding proteins, free spectrin is degraded, leading to spectrin deficiency. The spectrin protein is a tetramer made up of alpha-beta dimers. Mutations of alpha-spectrin are associated with recessive forms of HS, whereas mutations of beta-spectrin occur in autosomal dominant forms of HS. [1][2] Synthesis of alpha-spectrin is threefold greater than that of beta-spectrin.
- The excess alpha chains normally are degraded. Heterozygotes for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the heterozygous state because synthesis of beta-spectrin is the rate-limiting factor. Red cell membranes isolated from individuals with autosomal recessive HS have only 40-50% of the normal amount of spectrin (relative to band protein 3). In the autosomal dominant form of HS, red cell spectrin levels range from 60-80% of normal. Approximately 50% of patients with severe recessive HS have a point mutation at codon (969) that results in an amino acid substitution (alanine [Ala]/aspartic acid [Asp]) at the corresponding site in the alpha-spectrin protein. This leads to a defective binding of spectrin to protein 4.1. Mutations involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency. Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo proteolytic degradation.
- Ankyrin defects: HS is described in patients with translocation of chromosome 8 or deletion of the short arm of chromosome 8, where the ankyrin gene is located. Patients with HS and deletion of chromosome 8 have a decrease in red cell ankyrin content. Ankyrin is the principal binding site for spectrin on the red cell membrane. Studies of cytoskeletal protein assembly in reticulocytes indicate that ankyrin deficiency leads to decreased incorporation of spectrin. In HS caused by ankyrin deficiency, a proportional decrease in spectrin content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with autosomal dominant HS have combined spectrin and ankyrin deficiency and the two proteins are diminished equally.
- Band 3 deficiency: Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the erythrocyte membrane. In some individuals with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable.
- Protein 4.2 (pallidin) deficiency: Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. RBC morphology in these cases is characterized by spherocytes, elliptocytes, or sphero-ovalocytes. Deficiency of protein 4.2 in HS is relatively common in Japan. One mutation that appears to be common in the Japanese population (resulting in protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype.
- Aquaporin-1: In addition to abnormal levels of proteins affected by mutations, patients with HS may demonstrate aberrant distribution of other proteins in erythrocytes. Crisp et al found reduced expression of the water channel protein aquaporin-1 (AQP1) in the membranes of erythrocytes from patients with HS, compared with normal controls. The AQP1 content in erythrocyte membranes correlated with the clinical severity of HS. [7]
- Red blood cell antibodies: Using a mitogen-stimulated direct antiglobulin test, Zaninoni and colleagues found RBC antibodies in 61% of patients with HS. Patients with RBC-bound IgG of more than 250 ng/mL (the positive threshold of autoimmune hemolytic anemia) had increased numbers of spherocytes and mainly had spectrin deficiency. These researchers concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these antibodies have a pathogenic role in RBC opsonization and removal by the spleen.[3]
References
- ↑ Perrotta, S.; Della Ragione, F.; Rossi, F.; Avvisati, R. A.; Di Pinto, D.; De Mieri, G.; Scianguetta, S.; Mancusi, S.; De Falco, L.; Marano, V.; Iolascon, A. (2009). "-spectrinBari: a truncated -chain responsible for dominant hereditary spherocytosis". Haematologica. 94 (12): 1753–1757. doi:10.3324/haematol.2009.010124. ISSN 0390-6078.
- ↑ Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B (2009). "Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA". Br J Haematol. 146 (3): 326–32. doi:10.1111/j.1365-2141.2009.07759.x. PMID 19538529.
- ↑ Zaninoni A, Vercellati C, Imperiali FG, Marcello AP, Fattizzo B, Fermo E; et al. (2015). "Detection of red blood cell antibodies in mitogen-stimulated cultures from patients with hereditary spherocytosis". Transfusion. 55 (12): 2930–8. doi:10.1111/trf.13257. PMID 26259504.