RBCC

Full text data of SPTA1

SPTA1 (SPTA) [Confidence: high (present in two of the MS resources)]
Spectrin alpha chain, erythrocytic 1 (Erythroid alpha-spectrin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00220741
IPI00220741 Spectrin alpha chain, erythrocyte Spectrin alpha chain, erythrocyte membrane 45 11 173 139 179 9 155 17 248 29 114 92 24 84 6 29 71 165 13 125 cytoskeleton n/a found at its expected molecular weight found at molecular weight

UniProt P02549
ID SPTA1_HUMAN Reviewed; 2419 AA.
AC P02549; Q15514; Q5VYL1; Q5VYL2; Q6LDY5;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 5.
DT 22-JAN-2014, entry version 171.
DE RecName: Full=Spectrin alpha chain, erythrocytic 1;
DE AltName: Full=Erythroid alpha-spectrin;
GN Name=SPTA1; Synonyms=SPTA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANTS
RP ALA-1163 AND ARG-1568.
RX PubMed=1689726;
RA Sahr K.E., Laurila P., Kotula L., Scarpa A.L., Coupal E., Leto T.L.,
RA Linnenbach A.J., Winkelmann J.C., Speicher D.W., Marchesi V.T.,
RA Curtis P.J., Forget B.G.;
RT "The complete cDNA and polypeptide sequences of human erythroid alpha-
RT spectrin.";
RL J. Biol. Chem. 265:4434-4443(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 7-533, AND VARIANTS EL2 PRO-260;
RP PRO-261 AND PRO-471.
RX PubMed=2794061; DOI=10.1172/JCI114291;
RA Sahr K.E., Tobe T., Scarpa A., Laughinghouse K., Marchesi S.L.,
RA Agre P., Linnenbach A.J., Marchesi V.T., Forget B.G.;
RT "Sequence and exon-intron organization of the DNA encoding the alpha I
RT domain of human spectrin. Application to the study of mutations
RT causing hereditary elliptocytosis.";
RL J. Clin. Invest. 84:1243-1252(1989).
RN [4]
RP PROTEIN SEQUENCE OF 7-601.
RX PubMed=6654896;
RA Speicher D.W., Davis G., Marchesi V.T.;
RT "Structure of human erythrocyte spectrin. II. The sequence of the
RT alpha-I domain.";
RL J. Biol. Chem. 258:14938-14947(1983).
RN [5]
RP PROTEIN SEQUENCE OF 7-125.
RX PubMed=6654895;
RA Speicher D.W., Davis G., Yurchenco P.D., Marchesi V.T.;
RT "Structure of human erythrocyte spectrin. I. Isolation of the alpha-I
RT domain and its cyanogen bromide peptides.";
RL J. Biol. Chem. 258:14931-14937(1983).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 320-450.
RX PubMed=3458204; DOI=10.1073/pnas.83.8.2397;
RA Linnenbach A.J., Speicher D.W., Marchesi V.T., Forget B.G.;
RT "Cloning of a portion of the chromosomal gene for human erythrocyte
RT alpha-spectrin by using a synthetic gene fragment.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:2397-2401(1986).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1451-1688, AND VARIANT ARG-1568.
RX PubMed=3000887; DOI=10.1016/0378-1119(85)90191-X;
RA Curtis P.J., Palumbo A., Ming J., Fraser P.J., Cioe L., Meo P.,
RA Shane S., Rovera G.;
RT "Sequence comparison of human and murine erythrocyte alpha-spectrin
RT cDNA.";
RL Gene 36:357-362(1985).
RN [8]
RP PARTIAL PROTEIN SEQUENCE.
RX PubMed=6472478; DOI=10.1038/311177a0;
RA Speicher D.W., Marchesi V.T.;
RT "Erythrocyte spectrin is comprised of many homologous triple helical
RT segments.";
RL Nature 311:177-180(1984).
RN [9]
RP PROTEIN SEQUENCE OF 7-16; 46-55; 680-689; 1047-1056 AND 1922-1931.
RX PubMed=1634521;
RA Speicher D.W., Weglarz L., DeSilva T.M.;
RT "Properties of human red cell spectrin heterodimer (side-to-side)
RT assembly and identification of an essential nucleation site.";
RL J. Biol. Chem. 267:14775-14782(1992).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 19-28; 39-44 AND 50-59.
RX PubMed=7929303;
RA Lusitani D.M., Qtaishat N., LaBrake C.C., Yu R.N., Davis J.,
RA Kelley M.R., Fung L.W.-M.;
RT "The first human alpha-spectrin structural domain begins with
RT serine.";
RL J. Biol. Chem. 269:25955-25958(1994).
RN [11]
RP IDENTIFICATION OF PROBABLE FRAMESHIFT IN 2408-2419.
RA Gibson T.J.;
RL Unpublished observations (MAR-1995).
RN [12]
RP INTERACTION WITH FASLG.
RX PubMed=19807924; DOI=10.1186/1471-2172-10-53;
RA Voss M., Lettau M., Janssen O.;
RT "Identification of SH3 domain interaction partners of human FasL
RT (CD178) by phage display screening.";
RL BMC Immunol. 10:53-53(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP STRUCTURE BY NMR OF 1-156, AND SUBUNIT.
RX PubMed=12672815; DOI=10.1074/jbc.M300617200;
RA Park S., Caffrey M.S., Johnson M.E., Fung L.W.-M.;
RT "Solution structural studies on human erythrocyte alpha-spectrin
RT tetramerization site.";
RL J. Biol. Chem. 278:21837-21844(2003).
RN [15]
RP REVIEW ON VARIANTS.
RX PubMed=8844207;
RX DOI=10.1002/(SICI)1098-1004(1996)8:2<97::AID-HUMU1>3.3.CO;2-W;
RA Maillet P., Alloisio N., Morle L., Delaunay J.;
RT "Spectrin mutations in hereditary elliptocytosis and hereditary
RT spherocytosis.";
RL Hum. Mutat. 8:97-107(1996).
RN [16]
RP VARIANT EL2 SER-24.
RX PubMed=8018926;
RA Parquet N., Devaux I., Boulanger L., Galand C., Boivin P.,
RA Lecomte M.-C., Dhermy D., Garbarz M.;
RT "Identification of three novel spectrin alpha I/74 mutations in
RT hereditary elliptocytosis: further support for a triple-stranded
RT folding unit model of the spectrin heterodimer contact site.";
RL Blood 84:303-308(1994).
RN [17]
RP VARIANTS EL2 CYS-28; HIS-28; LEU-28 AND SER-28.
RX PubMed=1679439; DOI=10.1172/JCI115371;
RA Coetzer T.L., Sahr K., Prchal J., Blacklock H., Peterson L., Koler R.,
RA Doyle J., Manaster J., Palek J.;
RT "Four different mutations in codon 28 of alpha spectrin are associated
RT with structurally and functionally abnormal spectrin alpha I/74 in
RT hereditary elliptocytosis.";
RL J. Clin. Invest. 88:743-749(1991).
RN [18]
RP VARIANT EL2 SER-28, AND VARIANT HPP ARG-48.
RX PubMed=1878597;
RA Floyd P.B., Gallagher P.G., Valentino L.A., Davis M., Marchesi S.L.,
RA Forget B.G.;
RT "Heterogeneity of the molecular basis of hereditary pyropoikilocytosis
RT and hereditary elliptocytosis associated with increased levels of the
RT spectrin alpha I/74-kilodalton tryptic peptide.";
RL Blood 78:1364-1372(1991).
RN [19]
RP VARIANT EL2 SER-45.
RX PubMed=2568862;
RA Lecomte M.-C., Garbarz M., Grandchamp B., Feo C., Gautero H.,
RA Devaux I., Bournier O., Galand C., D'Auriol L., Galibert F.,
RA Sahr K.E., Forget B.G., Boivin P., Dhermy D.;
RT "Sp alpha I/78: a mutation of the alpha I spectrin domain in a white
RT kindred with HE and HPP phenotypes.";
RL Blood 74:1126-1133(1989).
RN [20]
RP VARIANT EL2/HPP PRO-207.
RX PubMed=1541680; DOI=10.1172/JCI115669;
RA Gallagher P.G., Tse W.T., Coetzer T., Lecomte M.-C., Garbarz M.,
RA Zarkowsky H.S., Baruchel A., Ballas S.K., Dhermy D., Palek J.,
RA Forget B.G.;
RT "A common type of the spectrin alpha I 46-50a-kD peptide abnormality
RT in hereditary elliptocytosis and pyropoikilocytosis is associated with
RT a mutation distant from the proteolytic cleavage site. Evidence for
RT the functional importance of the triple helical model of spectrin.";
RL J. Clin. Invest. 89:892-898(1992).
RN [21]
RP VARIANT VAL-1858.
RX PubMed=8486776; DOI=10.1172/JCI116432;
RA Wilmotte R., Marechal J., Morle L., Baklouti F., Philippe N.,
RA Kastally R., Kotula L., Delaunay J., Alloisio N.;
RT "Low expression allele alpha LELY of red cell spectrin is associated
RT with mutations in exon 40 (alpha V/41 polymorphism) and intron 45 and
RT with partial skipping of exon 46.";
RL J. Clin. Invest. 91:2091-2096(1993).
RN [22]
RP VARIANT EL2 BARCELONA PRO-469.
RX PubMed=8364215;
RA dalla Venezia N., Alloisio N., Forissier A., Denoroy L., Aymerich M.,
RA Vives-Corrons J.L., Besalduch J., Besson I., Delaunay J.;
RT "Elliptopoikilocytosis associated with the alpha 469 His-->Pro
RT mutation in spectrin Barcelona (alpha I/50-46b).";
RL Blood 82:1661-1665(1993).
RN [23]
RP VARIANT CAGLIARI GLY-2025.
RX PubMed=8226774;
RA Sahr K.E., Coetzer T.L., Moy L.S., Derick L.H., Chishti A.H.,
RA Jarolim P., Lorenzo F., del Giudice E.M., Iolascon A., Gallanello R.,
RA Cao A., Delaunay J., Liu S.-C., Palek J.;
RT "Spectrin Cagliari: an Ala-->Gly substitution in helix 1 of beta
RT spectrin repeat 17 that severely disrupts the structure and self-
RT association of the erythrocyte spectrin heterodimer.";
RL J. Biol. Chem. 268:22656-22662(1993).
RN [24]
RP VARIANT EL2 CULOZ VAL-46, AND VARIANT EL2 LYON PHE-49.
RX PubMed=2384601; DOI=10.1172/JCI114743;
RA Morle L., Roux A.-F., Alloisio N., Pothier B., Starck J., Denoroy J.,
RA Morle F., Rudigoz R.-C., Forget B.G., Delaunay J., Godet J.;
RT "Two elliptocytogenic alpha I/74 variants of the spectrin alpha I
RT domain. Spectrin Culoz (GGT-->GTT; alpha I 40 Gly-->Val) and spectrin
RT Lyon (CTT-->TTT; alpha I 43 Leu-->Phe).";
RL J. Clin. Invest. 86:548-554(1990).
RN [25]
RP VARIANT EL2 JENDOUBA GLU-791.
RX PubMed=1638030;
RA Alloisio N., Wilmotte R., Morle L., Baklouti F., Marechal J.,
RA Ducluzeau M.-T., Denoroy L., Feo C., Forget B.G., Kastally R.,
RA Delaunay J.;
RT "Spectrin Jendouba: an alpha II/31 spectrin variant that is associated
RT with elliptocytosis and carries a mutation distant from the dimer
RT self-association site.";
RL Blood 80:809-815(1992).
RN [26]
RP VARIANT EL2 TUNIS TRP-41.
RX PubMed=2568861;
RA Morle L., Morle F., Roux A.-F., Godet J., Forget B.G., Denoroy L.,
RA Garbarz M., Dhermy D., Kastally R., Delaunay J.;
RT "Spectrin Tunis (Sp alpha I/78), an elliptocytogenic variant, is due
RT to the CGG-->TGG codon change (Arg-->Trp) at position 35 of the alpha
RT I domain.";
RL Blood 74:828-832(1989).
RN [27]
RP VARIANT EL2 GENOVA TRP-34.
RX PubMed=8193371;
RA Perrotta S., del Giudice E.M., Alloisio N., Sciarratta G., Pinto L.,
RA Delaunay J., Cutillo S., Lolascon A.;
RT "Mild elliptocytosis associated with the alpha 34 Arg-->Trp mutation
RT in spectrin Genova (alpha I/74).";
RL Blood 83:3346-3349(1994).
RN [28]
RP VARIANT EL2 ANASTASIA THR-45.
RX PubMed=7772539;
RA Perrotta S., Iolascon A., de Angelis F., Pagano L., Colonna G.,
RA Cutillo S., del Giudice E.M.;
RT "Spectrin Anastasia (alpha I/78): a new spectrin variant (alpha 45
RT Arg-->Thr) with moderate elliptocytogenic potential.";
RL Br. J. Haematol. 89:933-936(1995).
CC -!- FUNCTION: Spectrin is the major constituent of the cytoskeletal
CC network underlying the erythrocyte plasma membrane. It associates
CC with band 4.1 and actin to form the cytoskeletal superstructure of
CC the erythrocyte plasma membrane.
CC -!- SUBUNIT: Composed of non-homologous chains, alpha and beta, which
CC aggregate side-to-side in an antiparallel fashion to form dimers,
CC tetramers, and higher polymers. Interacts with FASLG.
CC -!- INTERACTION:
CC Q8IZP0:ABI1; NbExp=2; IntAct=EBI-375617, EBI-375446;
CC Q01082:SPTBN1; NbExp=3; IntAct=EBI-375617, EBI-351561;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm, cell
CC cortex.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P02549-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P02549-2; Sequence=VSP_037662;
CC Note=Gene prediction based on EST data;
CC -!- DISEASE: Elliptocytosis 2 (EL2) [MIM:130600]: A Rhesus-unlinked
CC form of hereditary elliptocytosis, a genetically heterogeneous,
CC autosomal dominant hematologic disorder. It is characterized by
CC variable hemolytic anemia and elliptical or oval red cell shape.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Hereditary pyropoikilocytosis (HPP) [MIM:266140]:
CC Autosomal recessive hematologic disorder characterized by
CC hemolytic anemia, microspherocytosis, poikilocytosis, and an
CC unusual thermal sensitivity of red cells. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Spherocytosis 3 (SPH3) [MIM:270970]: Spherocytosis is a
CC hematologic disorder leading to chronic hemolytic anemia and
CC characterized by numerous abnormally shaped erythrocytes which are
CC generally spheroidal. SPH3 is characterized by severe hemolytic
CC anemia. Inheritance is autosomal recessive. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: This complex is anchored to the cytoplasmic face of
CC the plasma membrane via another protein, ankyrin, which binds to
CC beta-spectrin and mediates the binding of the whole complex to a
CC transmembrane protein band 3. The interaction of erythrocyte
CC spectrin with other proteins through specific binding domains lead
CC to the formation of an extensive subplasmalemmal meshwork which is
CC thought to be responsible for the maintenance of the biconcave
CC shape of human erythrocytes, for the regulation of plasma membrane
CC components and for the maintenance of the lipid asymmetry of the
CC plasma membrane.
CC -!- SIMILARITY: Belongs to the spectrin family.
CC -!- SIMILARITY: Contains 3 EF-hand domains.
CC -!- SIMILARITY: Contains 1 SH3 domain.
CC -!- SIMILARITY: Contains 21 spectrin repeats.
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DR EMBL; M61826; AAA60994.1; -; Genomic_DNA.
DR EMBL; M61776; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61777; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61778; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61779; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61780; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61781; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61782; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61783; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61852; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61784; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61785; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61787; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61788; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61789; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61791; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61792; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61793; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61794; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61795; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61796; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61797; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61798; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61799; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61800; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61801; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61802; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61803; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61804; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61805; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61806; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61807; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61808; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61809; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61810; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61811; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61812; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61814; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61815; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61816; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61817; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61818; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61819; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61820; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61821; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61822; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61823; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61824; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61825; AAA60994.1; JOINED; Genomic_DNA.
DR EMBL; M61877; AAA60577.1; -; mRNA.
DR EMBL; AL353894; CAH73936.1; -; Genomic_DNA.
DR EMBL; AL353894; CAH73937.1; -; Genomic_DNA.
DR EMBL; M29994; AAA60575.1; -; Genomic_DNA.
DR EMBL; M29983; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29984; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29985; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29986; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29987; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29988; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29989; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29990; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29991; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29992; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M29993; AAA60575.1; JOINED; Genomic_DNA.
DR EMBL; M13233; AAA53103.1; -; Genomic_DNA.
DR EMBL; M11049; AAA60569.1; -; mRNA.
DR PIR; A35716; SJHUA.
DR RefSeq; NP_003117.2; NM_003126.2.
DR UniGene; Hs.119825; -.
DR PDB; 1OWA; NMR; -; A=1-156.
DR PDB; 3LBX; X-ray; 2.80 A; A=1-158.
DR PDBsum; 1OWA; -.
DR PDBsum; 3LBX; -.
DR ProteinModelPortal; P02549; -.
DR SMR; P02549; 1-953, 993-1034, 1049-2264, 2267-2415.
DR DIP; DIP-1020N; -.
DR DIP; DIP-17031N; -.
DR IntAct; P02549; 12.
DR MINT; MINT-7211599; -.
DR STRING; 9606.ENSP00000357130; -.
DR PhosphoSite; P02549; -.
DR DMDM; 308153675; -.
DR PaxDb; P02549; -.
DR PRIDE; P02549; -.
DR DNASU; 6708; -.
DR Ensembl; ENST00000368147; ENSP00000357129; ENSG00000163554.
DR Ensembl; ENST00000368148; ENSP00000357130; ENSG00000163554.
DR GeneID; 6708; -.
DR KEGG; hsa:6708; -.
DR UCSC; uc001fst.1; human.
DR CTD; 6708; -.
DR GeneCards; GC01M158580; -.
DR H-InvDB; HIX0028529; -.
DR HGNC; HGNC:11272; SPTA1.
DR HPA; HPA028048; -.
DR MIM; 130600; phenotype.
DR MIM; 182860; gene.
DR MIM; 266140; phenotype.
DR MIM; 270970; phenotype.
DR neXtProt; NX_P02549; -.
DR Orphanet; 98864; Common hereditary elliptocytosis.
DR Orphanet; 98867; Hereditary pyropoikilocytosis.
DR Orphanet; 822; Hereditary spherocytosis.
DR PharmGKB; PA36101; -.
DR eggNOG; NOG237318; -.
DR HOGENOM; HOG000246965; -.
DR HOVERGEN; HBG059266; -.
DR InParanoid; P02549; -.
DR KO; K06114; -.
DR OMA; SINKDWW; -.
DR OrthoDB; EOG7GXP9K; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_127416; Developmental Biology.
DR ChiTaRS; SPTA1; human.
DR EvolutionaryTrace; P02549; -.
DR GeneWiki; Spectrin,_alpha_1; -.
DR GenomeRNAi; 6708; -.
DR NextBio; 26158; -.
DR PRO; PR:P02549; -.
DR ArrayExpress; P02549; -.
DR Bgee; P02549; -.
DR CleanEx; HS_SPTA1; -.
DR Genevestigator; P02549; -.
DR GO; GO:0032437; C:cuticular plate; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031235; C:intrinsic to cytoplasmic side of plasma membrane; TAS:BHF-UCL.
DR GO; GO:0008091; C:spectrin; TAS:ProtInc.
DR GO; GO:0014731; C:spectrin-associated cytoskeleton; IDA:BHF-UCL.
DR GO; GO:0051015; F:actin filament binding; TAS:ProtInc.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0051693; P:actin filament capping; IEA:UniProtKB-KW.
DR GO; GO:0007015; P:actin filament organization; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0030097; P:hemopoiesis; IEA:Ensembl.
DR GO; GO:0002260; P:lymphocyte homeostasis; IEA:Ensembl.
DR GO; GO:0007009; P:plasma membrane organization; IEA:Ensembl.
DR GO; GO:0006779; P:porphyrin-containing compound biosynthetic process; IEA:Ensembl.
DR GO; GO:0032092; P:positive regulation of protein binding; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0008360; P:regulation of cell shape; IEA:UniProtKB-KW.
DR Gene3D; 1.10.238.10; -; 2.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR014837; EF-hand_Ca_insen.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR013315; Spectrin_alpha_SH3.
DR InterPro; IPR002017; Spectrin_repeat.
DR Pfam; PF08726; EFhand_Ca_insen; 1.
DR Pfam; PF00018; SH3_1; 1.
DR Pfam; PF00435; Spectrin; 20.
DR PRINTS; PR01887; SPECTRNALPHA.
DR SMART; SM00054; EFh; 2.
DR SMART; SM00326; SH3; 1.
DR SMART; SM00150; SPEC; 20.
DR SUPFAM; SSF50044; SSF50044; 1.
DR PROSITE; PS50222; EF_HAND_2; 3.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Actin capping; Actin-binding; Alternative splicing;
KW Calcium; Cell shape; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Elliptocytosis;
KW Hereditary hemolytic anemia; Metal-binding; Polymorphism;
KW Pyropoikilocytosis; Reference proteome; Repeat; SH3 domain.
FT CHAIN 1 2419 Spectrin alpha chain, erythrocytic 1.
FT /FTId=PRO_0000073452.
FT REPEAT 19 51 Spectrin 1.
FT REPEAT 53 156 Spectrin 2.
FT REPEAT 158 262 Spectrin 3.
FT REPEAT 264 368 Spectrin 4.
FT REPEAT 370 474 Spectrin 5.
FT REPEAT 476 580 Spectrin 6.
FT REPEAT 582 685 Spectrin 7.
FT REPEAT 687 791 Spectrin 8.
FT REPEAT 793 897 Spectrin 9.
FT REPEAT 899 968 Spectrin 10.
FT DOMAIN 977 1036 SH3.
FT REPEAT 1082 1181 Spectrin 11.
FT REPEAT 1183 1287 Spectrin 12.
FT REPEAT 1289 1393 Spectrin 13.
FT REPEAT 1395 1498 Spectrin 14.
FT REPEAT 1500 1605 Spectrin 15.
FT REPEAT 1607 1711 Spectrin 16.
FT REPEAT 1713 1817 Spectrin 17.
FT REPEAT 1819 1926 Spectrin 18.
FT REPEAT 1928 2033 Spectrin 19.
FT REPEAT 2043 2147 Spectrin 20.
FT REPEAT 2157 2258 Spectrin 21.
FT DOMAIN 2271 2306 EF-hand 1.
FT DOMAIN 2314 2349 EF-hand 2.
FT DOMAIN 2352 2386 EF-hand 3.
FT CA_BIND 2284 2295 1 (Potential).
FT CA_BIND 2327 2338 2 (Potential).
FT VAR_SEQ 1889 1891 Missing (in isoform 2).
FT /FTId=VSP_037662.
FT VARIANT 24 24 I -> S (in EL2; Lograno).
FT /FTId=VAR_001324.
FT VARIANT 28 28 R -> C (in EL2).
FT /FTId=VAR_001328.
FT VARIANT 28 28 R -> H (in EL2; Corbeil;
FT dbSNP:rs28934004).
FT /FTId=VAR_001325.
FT VARIANT 28 28 R -> L (in EL2).
FT /FTId=VAR_001326.
FT VARIANT 28 28 R -> S (in EL2; dbSNP:rs28934005).
FT /FTId=VAR_001327.
FT VARIANT 31 31 V -> A (in EL2; Marseille).
FT /FTId=VAR_001329.
FT VARIANT 34 34 R -> W (in EL2; Genova).
FT /FTId=VAR_001330.
FT VARIANT 41 41 R -> W (in EL2; Tunis).
FT /FTId=VAR_001331.
FT VARIANT 45 45 R -> S (in EL2; Clichy).
FT /FTId=VAR_001332.
FT VARIANT 45 45 R -> T (in EL2; Anastasia).
FT /FTId=VAR_001333.
FT VARIANT 46 46 G -> V (in EL2; Culoz).
FT /FTId=VAR_001334.
FT VARIANT 48 48 K -> R (in HPP).
FT /FTId=VAR_001335.
FT VARIANT 49 49 L -> F (in EL2; Lyon).
FT /FTId=VAR_001336.
FT VARIANT 109 109 S -> F (in dbSNP:rs3737521).
FT /FTId=VAR_038506.
FT VARIANT 151 151 G -> D (in EL2; Ponte de Sor).
FT /FTId=VAR_001337.
FT VARIANT 152 152 D -> N (in dbSNP:rs16840544).
FT /FTId=VAR_038507.
FT VARIANT 154 154 L -> LL (in EL2).
FT /FTId=VAR_001338.
FT VARIANT 207 207 L -> P (in EL2 and HPP; Saint-Louis;
FT dbSNP:rs121918643).
FT /FTId=VAR_001339.
FT VARIANT 260 260 L -> P (in EL2; Nigerian).
FT /FTId=VAR_001340.
FT VARIANT 261 261 S -> P (in EL2).
FT /FTId=VAR_001341.
FT VARIANT 469 469 H -> P (in EL2; Barcelona).
FT /FTId=VAR_001342.
FT VARIANT 469 469 Missing (in EL2; Alexandria).
FT /FTId=VAR_001343.
FT VARIANT 471 471 Q -> P (in EL2).
FT /FTId=VAR_001344.
FT VARIANT 701 701 R -> H (in dbSNP:rs12090314).
FT /FTId=VAR_001345.
FT VARIANT 766 766 A -> T (in dbSNP:rs11265047).
FT /FTId=VAR_038508.
FT VARIANT 791 791 D -> E (in EL2; Jendouba;
FT dbSNP:rs7418956).
FT /FTId=VAR_001346.
FT VARIANT 809 809 I -> V (in dbSNP:rs7547313).
FT /FTId=VAR_001347.
FT VARIANT 853 853 T -> R (in dbSNP:rs35121052).
FT /FTId=VAR_001348.
FT VARIANT 957 957 A -> V (in dbSNP:rs34706737).
FT /FTId=VAR_038509.
FT VARIANT 970 970 A -> D (in dbSNP:rs35948326).
FT /FTId=VAR_001349.
FT VARIANT 1163 1163 S -> A (in dbSNP:rs2482965).
FT /FTId=VAR_038510.
FT VARIANT 1330 1330 R -> I (in dbSNP:rs34214405).
FT /FTId=VAR_038511.
FT VARIANT 1568 1568 C -> R (in dbSNP:rs863931).
FT /FTId=VAR_038512.
FT VARIANT 1693 1693 K -> Q (in dbSNP:rs857725).
FT /FTId=VAR_059199.
FT VARIANT 1836 1836 N -> S (in dbSNP:rs16830483).
FT /FTId=VAR_059200.
FT VARIANT 1858 1858 L -> V (in dbSNP:rs3737515).
FT /FTId=VAR_001350.
FT VARIANT 2025 2025 A -> G (in Cagliari).
FT /FTId=VAR_001351.
FT VARIANT 2265 2265 I -> T (in dbSNP:rs952094).
FT /FTId=VAR_059201.
FT CONFLICT 119 130 Missing (in Ref. 3; AAA60575).
FT CONFLICT 395 395 A -> G (in Ref. 3; AAA60575).
FT CONFLICT 1410 1410 W -> R (in Ref. 1; AAA60577/AAA60994).
FT CONFLICT 1570 1570 Missing (in Ref. 1; AAA60577/AAA60994 and
FT 7; AAA60569).
FT CONFLICT 1891 1891 Q -> H (in Ref. 1; AAA60577/AAA60994).
FT CONFLICT 2400 2419 GRSHLSGYDYVGFTNSYFGN -> VEAISLAMTTLASPIPT
FT LATNKQLLVDRRKS (in Ref. 1; AAA60577/
FT AAA60994).
FT STRAND 12 14
FT HELIX 24 26
FT HELIX 27 30
FT HELIX 31 33
FT HELIX 34 77
FT HELIX 87 118
FT HELIX 126 156
SQ SEQUENCE 2419 AA; 280014 MW; B60680145C58DF55 CRC64;
MEQFPKETVV ESSGPKVLET AEEIQERRQE VLTRYQSFKE RVAERGQKLE DSYHLQVFKR
DADDLGKWIM EKVNILTDKS YEDPTNIQGK YQKHQSLEAE VQTKSRLMSE LEKTREERFT
MGHSAHEETK AHIEELRHLW DLLLELTLEK GDQLLRALKF QQYVQECADI LEWIGDKEAI
ATSVELGEDW ERTEVLHKKF EDFQVELVAK EGRVVEVNQY ANECAEENHP DLPLIQSKQN
EVNAAWERLR GLALQRQKAL SNAANLQRFK RDVTEAIQWI KEKEPVLTSE DYGKDLVASE
GLFHSHKGLE RNLAVMSDKV KELCAKAEKL TLSHPSDAPQ IQEMKEDLVS SWEHIRALAT
SRYEKLQATY WYHRFSSDFD ELSGWMNEKT AAINADELPT DVAGGEVLLD RHQQHKHEID
SYDDRFQSAD ETGQDLVNAN HEASDEVREK MEILDNNWTA LLELWDERHR QYEQCLDFHL
FYRDSEQVDS WMSRQEAFLE NEDLGNSLGS AEALLQKHED FEEAFTAQEE KIITVDKTAT
KLIGDDHYDS ENIKAIRDGL LARRDALREK AATRRRLLKE SLLLQKLYED SDDLKNWINK
KKKLADDEDY KDIQNLKSRV QKQQVFEKEL AVNKTQLENI QKTGQEMIEG GHYASDNVTT
RLSEVASLWE ELLEATKQKG TQLHEANQQL QFENNAEDLQ RWLEDVEWQV TSEDYGKGLA
EVQNRLRKHG LLESAVAARQ DQVDILTDLA AYFEEIGHPD SKDIRARQES LVCRFEALKE
PLATRKKKLL DLLHLQLICR DTEDEEAWIQ ETEPSATSTY LGKDLIASKK LLNRHRVILE
NIASHEPRIQ EITERGNKMV EEGHFAAEDV ASRVKSLNQN MESLRARAAR RQNDLEANVQ
FQQYLADLHE AETWIREKEP IVDNTNYGAD EEAAGALLKK HEAFLLDLNS FGDSMKALRN
QANACQQQQA APVEGVAGEQ RVMALYDFQA RSPREVTMKK GDVLTLLSSI NKDWWKVEAA
DHQGIVPAVY VRRLAHDEFP MLPQRRREEP GNITQRQEQI ENQYRSLLDR AEERRRRLLQ
RYNEFLLAYE AGDMLEWIQE KKAENTGVEL DDVWELQKKF DEFQKDLNTN EPRLRDINKV
ADDLLFEGLL TPEGAQIRQE LNSRWGSLQR LADEQRQLLG SAHAVEVFHR EADDTKEQIE
KKCQALSAAD PGSDLFSVQA LQRRHEGFER DLVPLGDKVT ILGETAERLS ESHPDATEDL
QRQKMELNEA WEDLQGRTKD RKESLNEAQK FYLFLSKARD LQNWISSIGG MVSSQELAED
LTGIEILLER HQEHRADMEA EAPTFQALED FSAELIDSGH HASPEIEKKL QAVKLERDDL
EKAWEKRKKI LDQCLELQMF QGNCDQVESW MVARENSLRS DDKSSLDSLE ALMKKRDDLD
KAITAQEGKI TDLEHFAESL IADEHYAKEE IATRLQRVLD RWKALKAQLI DERTKLGDYA
NLKQFYRDLE ELEEWISEML PTACDESYKD ATNIQRKYLK HQTFAHEVDG RSEQVHGVIN
LGNSLIECSA CDGNEEAMKE QLEQLKEHWD HLLERTNDKG KKLNEASRQQ RFNTSIRDFE
FWLSEAETLL AMKDQARDLA SAGNLLKKHQ LLEREMLARE DALKDLNTLA EDLLSSGTFN
VDQIVKKKDN VNKRFLNVQE LAAAHHEKLK EAYALFQFFQ DLDDEESWIE EKLIRVSSQD
YGRDLQGVQN LLKKHKRLEG ELVAHEPAIQ NVLDMAEKLK DKAAVGQEEI QLRLAQFVEH
WEKLKELAKA RGLKLEESLE YLQFMQNAEE EEAWINEKNA LAVRGDCGDT LAATQSLLMK
HEALENDFAV HETRVQNVCA QGEDILNKVL QEESQNKEIS SKIEALNEKT PSLAKAIAAW
KLQLEDDYAF QEFNWKADVV EAWIADKETS LKTNGNGADL GDFLTLLAKQ DTLDASLQSF
QQERLPEITD LKDKLISAQH NQSKAIEERY AALLKRWEQL LEASAVHRQK LLEKQLPLQK
AEDLFVEFAH KASALNNWCE KMEENLSEPV HCVSLNEIRQ LQKDHEDFLA SLARAQADFK
CLLELDQQIK ALGVPSSPYT WLTVEVLERT WKHLSDIIEE REQELQKEEA RQVKNFEMCQ
EFEQNASTFL QWILETRAYF LDGSLLKETG TLESQLEANK RKQKEIQAMK RQLTKIVDLG
DNLEDALILD IKYSTIGLAQ QWDQLYQLGL RMQHNLEQQI QAKDIKGVSE ETLKEFSTIY
KHFDENLTGR LTHKEFRSCL RGLNYYLPMV EEDEHEPKFE KFLDAVDPGR KGYVSLEDYT
AFLIDKESEN IKSSDEIENA FQALAEGKSY ITKEDMKQAL TPEQVSFCAT HMQQYMDPRG
RSHLSGYDYV GFTNSYFGN
//

MIM 130600
*RECORD*
*FIELD* NO
130600
*FIELD* TI
#130600 ELLIPTOCYTOSIS 2; EL2
;;ELLIPTOCYTOSIS, RHESUS-UNLINKED TYPE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreelliptocytosis-2 is caused by heterozygous mutation in the
alpha-spectrin gene (SPTA1; 182860) on chromosome 1q23.

For a general description and a discussion of genetic heterogeneity of
elliptocytosis (HE), see EL1 (611804).

CLINICAL FEATURES

In some families with HE, spectrin is abnormally heat-sensitive (Lux and
Wolfe, 1980). Coetzer and Zail (1981) studied spectrin in 4 cases of
hereditary elliptocytosis and found an abnormality of tryptic digestion
in 1. This patient was previously reported by Gomperts et al. (1973) as
an instance of hemolytic anemia due to HE.

Liu et al. (1982) examined erythrocytes from 18 patients with hereditary
elliptocytosis. In 8 patients (referred to as type 1), spectrin was
defective in dimer-dimer association as demonstrated in 2 ways. First,
spectrin dimer was increased and tetramer decreased; spectrin dimer
represented 15 to 33% of total spectrin compared with a normal range of
3 to 7%. Second, the equilibrium constants of spectrin dimer-dimer
association was decreased in both solution and in situ in red cell
membranes. In the other 10 patients (referred to as type 2), dimer-dimer
association was normal. Membrane skeletons, produced from both types of
elliptocytosis by Triton X-100 extraction of the red cell ghosts, were
unstable when mechanically shaken. Spectrin tetramers but not dimers can
crosslink actin.

Evans et al. (1983) studied a family in which 3 sibs had severe
transfusion-dependent, presumably homozygous elliptocytosis and both
parents had asymptomatic elliptocytosis. Red cell membranes of all 3
sibs showed an excess of spectrin dimers over tetramers in spectrin
extracts. Both parents showed an intermediate increase in spectrin
dimers.

In 7 black patients (from 5 unrelated families) with mild HE, Lecomte et
al. (1985) found an abnormal thermal sensitivity and an important defect
of spectrin dimer self-association. An excess of spectrin dimer and
deficient dimer-to-tetramer conversion were demonstrated. Peptide
patterns of crude spectrin showed a marked decrease in the 80-kD peptide
(previously identified as the dimer-dimer interaction domain of the
alpha chain) and a concomitant appearance of a novel 65-kD peptide.
Anti-alpha-spectrin antibodies showed that the latter peptide was
derived from the alpha chain. The patients were 3 unrelated adults, 2
children with hemolytic anemia, and the father of each child.

Lawler et al. (1984, 1985) described a molecular defect in the alpha
subunit of spectrin in a subset of patients with hereditary
elliptocytosis; the self-association of alpha-beta heterodimers to form
tetramers was defective.

Abnormality of alpha spectrin was reported by Ravindranath and Johnson
(1985) in a case of congenital hemolytic anemia.

Lambert and Zail (1987) also found a variant of the alpha subunit. Two
brothers with the poikilocytic variant of hereditary elliptocytosis were
found to have a defect in spectrin dimer association and a decreased
spectrin/band 3 ratio. The major abnormal tryptic peptides derived from
the alpha-I domain had lower molecular weights and more basic
isoelectric points than hitherto described. The propositus of Lambert
and Zail (1987) was a black South African miner.

In a 6-week-old black infant, Garbarz et al. (1986) found hemolytic
anemia with red cell fragmentation, poikilocytosis, and elliptocytosis.
Both parents and a brother of the propositus had compensated mild
hereditary elliptocytosis. Studies indicated that the proband was
homozygous for an alpha-I/65 spectrin variant whereas both parents were
heterozygous.

In a family with hereditary elliptocytosis, Lane et al. (1987) found
that alpha-spectrin subunits migrated anomalously in SDS-PAGE. The
quantity of the alpha-spectrin mutant, expressed as a percentage of the
total alpha spectrin, varied from 9.9 to 45.2% among 6 affected persons.
Other findings suggested that this new alpha-spectrin mutant is
responsible for decreased spectrin dimer-dimer association and for red
cell instability. The propositus, a 23-month-old boy, exhibited anemia,
hyperbilirubinemia requiring phototherapy, and striking red cell
poikilocytosis at birth. His only sib, a 4-year-old who had
hyperbilirubinemia at birth, exhibited elliptocytosis without
poikilocytosis at the time of study. The mother, 2 of her sibs, and the
maternal grandfather had elliptocytosis.

MAPPING

Morton (1956) defined the existence of Rh-linked (611804) and
Rh-unlinked forms of elliptocytosis and emphasized the usefulness of
linkage studies in demonstration of genetic heterogeneity.

Keats (1979) suggested that a second elliptocytosis locus unlinked to Rh
is on chromosome 1. She found a lod score of 1.97 for theta of 0.0 for
linkage with Duffy. From analysis of the data by a maximum likelihood
method, Rao et al. (1979) concluded that there is 'nonsignificant
evidence of linkage' of an Rh-unlinked form of elliptocytosis to
chromosome 1 (lod score, 2.08).

MOLECULAR GENETICS

By in situ hybridization, the SPTA1 gene was mapped to 1q22-1q25
(Huebner et al., 1985) in the region proposed by Keats (1979) for a
non-Rh-linked form of elliptocytosis. In patients with elliptocytosis,
Marchesi et al. (1987) identified heterozygous mutations in the SPTA1
gene (182860.0001-182860.0002). This is one of the first examples of
positive results from the 'candidate gene' approach to elucidating
etiopathogenesis.

*FIELD* SA
Lux et al. (1981)
*FIELD* RF
1. Coetzer, T.; Zail, S. S.: Tryptic digestion of spectrin in variants
of hereditary elliptocytosis. J. Clin. Invest. 67: 1241-1248, 1981.

2. Evans, J. P. M.; Baines, A. J.; Hann, I. M.; Al-Hakim, I.; Knowles,
S. M.; Hoffbrand, A. V.: Defective spectrin dimer-dimer association
in a family with transfusion dependent homozygous hereditary elliptocytosis. Brit.
J. Haemat. 54: 163-172, 1983.

3. Garbarz, M.; Lecomte, M. C.; Dhermy, D.; Feo, C.; Chaveroche, I.;
Gautero, H.; Bournier, O.; Picat, C.; Goepp, A.; Boivin, P.: Double
inheritance of an alpha I/65 spectrin variant in a child with homozygous
elliptocytosis. Blood 67: 1661-1667, 1986.

4. Gomperts, E. D.; Cayannis, F.; Metz, J.; Zail, S. S.: A red cell
membrane protein abnormality in hereditary elliptocytosis. Brit.
J. Haemat. 25: 415-420, 1973.

5. Huebner, K.; Palumbo, A. P.; Isobe, M.; Kozak, C. A.; Monaco, S.;
Rovera, G.; Croce, C. M.; Curtis, P. J.: The alpha-spectrin gene
is on chromosome 1 in mouse and man. Proc. Nat. Acad. Sci. 82: 3790-3793,
1985.

6. Keats, B. J. B.: Another elliptocytosis locus on chromosome 1? Hum.
Genet. 50: 227-230, 1979.

7. Lambert, S.; Zail, S.: A new variant of the alpha-subunit of spectrin
in hereditary elliptocytosis. Blood 69: 473-478, 1987.

8. Lane, P. A.; Shew, R. L.; Iarocci, T. A.; Mohandas, N.; Hays, T.;
Mentzer, W. C.: Unique alpha-spectrin mutant in a kindred with common
hereditary elliptocytosis. J. Clin. Invest. 79: 989-996, 1987.

9. Lawler, J.; Coetzer, T. L.; Palek, J.; Jacob, H. S.; Luban, N.
: Sp alpha(I/65): a new variant of the alpha subunit of spectrin in
hereditary elliptocytosis. Blood 66: 706-709, 1985.

10. Lawler, J.; Liu, S.-C.; Palek, J.; Prchal, J.: A molecular defect
in spectrin with a subset of patients with hereditary elliptocytosis:
alterations in the alpha-subunit domain involved in spectrin self-association. J.
Clin. Invest. 73: 1688-1695, 1984.

11. Lecomte, M.-C.; Dhermy, D.; Garbarz, M.; Feo, C.; Gautero, H.;
Bournier, O.; Picat, C.; Chaveroche, I.; Ester, A.; Galand, C.; Boivin,
P.: Pathologic and nonpathologic variants of the spectrin molecule
in two black families with hereditary elliptocytosis. Hum. Genet. 71:
351-357, 1985.

12. Liu, S.-C.; Palek, J.; Prchal, J. T.: Defective spectrin dimer-dimer
association in hereditary elliptocytosis. Proc. Nat. Acad. Sci. 79:
2072-2076, 1982.

13. Lux, S. E.; Wolfe, L. C.: Inherited disorders of the red cell
membrane skeleton. Pediat. Clin. N. Am. 27: 463-486, 1980.

14. Lux, S. E.; Wolfe, L. C.; Pease, B.; Tomaselli, M. B.; John, K.
M.; Bernstein, S. E.: Hemolytic anemias due to abnormalities of red
cell spectrin: a brief review. Prog. Clin. Biol. Res. 45: 159-168,
1981.

15. Marchesi, S. L.; Letsinger, J. T.; Speicher, D. W.; Marchesi,
V. T.; Agre, P.; Hyun, B.; Gulati, G.: Mutant forms of spectrin alpha-subunits
in hereditary elliptocytosis. J. Clin. Invest. 80: 191-198, 1987.

16. Morton, N. E.: The detection and estimation of linkage between
the genes for elliptocytosis and the Rh blood type. Am. J. Hum. Genet. 8:
80-96, 1956.

17. Rao, D. C.; Keats, B. J.; Lalouel, J. M.; Morton, N. E.; Yee,
S.: A maximum likelihood map of chromosome 1. Am. J. Hum. Genet. 31:
680-696, 1979.

18. Ravindranath, Y.; Johnson, R. M.: Altered spectrin association
and membrane fragility without abnormal spectrin heat sensitivity
in a case of congenital hemolytic anemia. Am. J. Hemat. 20: 53-65,
1985.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEMATOLOGY:
Elliptocytosis

MISCELLANEOUS:
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the spectrin, alpha, erythrocytic-1 gene (SPTA1,
182860.0001)

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/18/2011

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 04/30/2012
terry: 3/27/2012
terry: 3/18/2009
carol: 3/18/2009
mgross: 2/21/2008
terry: 4/30/1999
dkim: 7/21/1998
mimadm: 9/24/1994
carol: 5/13/1994
carol: 5/6/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/17/1992

MIM 182860
*RECORD*
*FIELD* NO
182860
*FIELD* TI
*182860 SPECTRIN, ALPHA, ERYTHROCYTIC 1; SPTA1
*FIELD* TX

DESCRIPTION

Spectrin, the predominant component of the membrane skeleton of the red
read morecell, is essential in determining the properties of the membrane
including its shape and deformability. It consists of 2 nonidentical
subunits, alpha (MW 240,000) and beta (MW 225,000; 182870) (Knowles et
al., 1984). Spectrin is present in the red cell membrane in a tetrameric
or oligomeric form through head-to-head self-association of heterodimers
that are linked by actin (see 102560) polymers and protein 4.1 (130500)
to form a 2-dimensional network. Ankyrin (612641) binds the skeleton to
the membrane lipid bilayer through its high-affinity association with
spectrin beta chains and the integral protein band 3 (109270) of the
lipid bilayer.

CLONING

Sahr et al. (1990) isolated overlapping cDNA clones for the entire
coding sequence of human erythroid alpha spectrin. The deduced
polypeptide contains 2,429 amino acids and, as noted by Speicher and
Marchesi (1984), is composed largely of homologous 106-amino acid repeat
units. The protein can be divided into 22 segments, 17 of which are
homologous. Only the very N-terminal 22 residues and the C-terminal 150
residues appear to be unrelated to the conserved repeat units.

GENE STRUCTURE

Kotula et al. (1991) noted that the SPTA gene spans 80 kb and includes
52 exons ranging in size from 18 to 684 bp. They mapped the exons and
the intron-exon junctions. The authors speculated that the absence of
correlation between exons and the 106-amino acid repeats characteristic
of the protein reflects the evolution of a spectrin-like gene from a
minigene early in the evolution of eukaryotes.

MAPPING

Birkenmeier et al. (1988) showed that the erythroid alpha-spectrin gene
is tightly linked to the spherocytosis locus on mouse chromosome 1,
suggesting that a defect in this gene is responsible for spherocytosis
in the mouse. Raeymaekers et al. (1988) found that alpha-spectrin is
linked to Duffy blood group (FY; 110700) on chromosome 1; the lod score
was 3.81 at theta = 0.0. By somatic cell hybrid studies, Huebner et al.
(1985) assigned the alpha-spectrin gene to chromosome 1 in both mouse
and man. By in situ hybridization, the human gene was localized to
1q22-q25. Since a non-Rh-linked form of elliptocytosis had been very
tentatively mapped (maximum lod score = 2.08) to this same region by
linkage to Duffy blood group (Keats, 1979; Rao et al., 1979), the defect
in that hematologic disorder may involve alpha spectrin. (As this turned
out to be the case, this is one of the first examples of positive
results from the 'candidate gene' approach to elucidating
etiopathogenesis.) In combination with in situ hybridization data, the
findings of Middleton-Price et al. (1988) suggested that SPTA may lie
within band 1q21. The gene was found to lie proximal to the breakpoint
at 1q23 in a balanced X;1 translocation. Another cell line showed 2
alpha-spectrin alleles, consistent with the location of alpha-spectrin
in the distal part of 1q21. Pakstis et al. (1989) presented linkage data
and analyzed the relationship between the SPTA1 locus and the anonymous
DNA fragment D1S75. Pairwise analyses estimated the maximum likelihood
of 12.8% recombination for the SPTA1/D1S75 interval with a peak lod
score of 5.04. In a linkage map of chromosome 1 prepared by Rouleau et
al. (1990), it was concluded that SPTA1 lies 17 cM proximal to Fy.

GENE FUNCTION

Kotula et al. (1991) noted that peptide mapping of spectrin partial
tryptic digests allowed division of the alpha- and beta-chains into 5
and 4 domains, respectively. The alpha-I and beta-I domains, which face
each other, participate in dimer self-association. Elliptocytosis can
result from changes in either the alpha-I or beta-I domain; changes in
either can result in weakened spectrin dimer self-association.

MOLECULAR GENETICS

Knowles et al. (1984) identified polymorphisms in the alpha-II domain of
spectrin in Caucasian and black individuals. The polymorphisms did not
produce anemia and did not appear to alter the expression of an
underlying spherocytosis or elliptocytosis. In family studies, the alpha
II 46,000 MW variations were consistent with mendelian inheritance.

- Elliptocytosis 2

In blacks, variants of the spectrin alpha subunit have been found:
alpha-I/74, alpha-I/46, and alpha-I/65 (Lawler et al., 1984; Lecomte et
al., 1985; Lawler et al., 1985). Alloisio et al. (1986) found the
alpha-I/65 variant in non-black persons in North Africa where a protein
4.1 defect had been found most often.

Marchesi et al. (1987) reviewed varieties of abnormal spectrins
(182860.0001-182860.0004) that have been found in hereditary
elliptocytosis (130600). All show impaired self-association to form
oligomers.

Iarocci et al. (1988) described a 4-year-old Yoruba boy in Nigeria who
at birth had severe poikilocytosis, hemolytic anemia, and
hyperbilirubinemia requiring exchange transfusion and phototherapy. The
poikilocytic anemia was found to be due to compound heterozygosity for 2
alpha-spectrin mutations. The authors indicated that 7 structural
mutations of alpha spectrin (designated I/74, I/65, I/61, I/50a, I/50b,
and I/43,42) as well as truncated alpha spectrin have been identified in
patients with hereditary elliptocytosis or hereditary pyropoikilocytosis
by SDS-PAGE evaluation of red cell membrane proteins or by analysis of
tryptic peptides following limited digestion.

One class of elliptocytogenic change is spectrin alpha(I/74) which is
characterized by an increase in the alpha-I 74-kD fragment at the
expense of the parent alpha-I 80-kD fragment. Spectrin Culoz
(182860.0006) and spectrin Lyon (182860.0007) are examples of alpha I/74
mutations of the alpha-spectrin chain.

Sahr et al. (1989) used PCR to amplify the appropriate exons in DNA from
individuals with 3 variants of hereditary elliptocytosis. In 1,
abnormality resulted from a duplication of leucine codon 148 in exon 4;
TTG-CTG to TTG-TTG-CTG (182860.0003). In 2 other unrelated cases, 2
separate single base changes were observed in exon 6: CTG to CCG
(leucine-to-proline) encoding residue 254, and TCC to CCC
(serine-to-proline) encoding residue 255. Furthermore, in 2 unrelated
individuals, a single base change of CAG to CCG (glutamine-to-proline)
encoding residue 465 in exon 11 was observed.

- Pyropoikilocytosis

Lecomte et al. (1985) described abnormality of alpha spectrin in 2 black
families with elliptocytosis and pyropoikilocytosis (266140). Marchesi
et al. (1986) also demonstrated abnormality of alpha spectrin in 2
kindreds with hereditary elliptocytosis. The clinical expression ranged
from mild elliptocytosis without hemolysis to severe poikilocytic
hemolytic anemia clinically resembling hereditary pyropoikilocytosis.

Lawler et al. (1988) described a severe form of pyropoikilocytosis in a
6-year-old black girl who was a compound heterozygote for 2 distinct
alpha-spectrin mutations, a previously detected mutation in tryptic
fragment 74 and a new mutation in tryptic fragment 61.

Lecomte et al. (1990) found a new alpha-spectrin variant in a child with
severe neonatal hemolytic anemia (182860.0021). The abnormality was
thought to be homozygous in the propositus who showed poikilocytosis. No
abnormality was detected in the parents, who came from the West Indies
and were thought to be unrelated.

- Spherocytosis Type 3

Wichterle et al. (1996) described compound heterozygosity for 2 splicing
mutations (182860.0022; 182860.0023) in the SPTA1 gene that caused
hereditary spherocytosis (270970).

Gallagher and Forget (1996) cataloged 25 alpha-spectrin mutations
reported in cases of hereditary elliptocytosis and hereditary
pyropoikilocytosis. Three were splicing mutations, 1 was a 3-bp
insertion, and the remainder were missense mutations. Gallagher and
Forget (1998) tabulated 2 SPTA1 mutations that cause hereditary
spherocytosis as contrasted with 19 mutations of the beta-spectrin gene
(SPTB; 182870) that are known to cause hereditary spherocytosis.
Gallagher and Forget (1998) tabulated 2 mutations of the SPTA gene that
caused hereditary spherocytosis.

GENOTYPE/PHENOTYPE CORRELATIONS

It has repeatedly been observed that the amount of mutant alpha chain is
variable in different individuals with hereditary elliptocytosis,
resulting in clinical pictures of variable severity. In a large Algerian
family with Sp-alpha(I/65) hereditary elliptocytosis, Guetarni et al.
(1990) demonstrated that the different levels are the result of
different percentages of the alpha-spectrin allele in trans. In an
informative sibship, they found 3 persons with a distinctly high level
of expression of the variant, suggesting the existence in trans of a
low-percentage alpha-allele (called LE allele for 'low expression'). In
contrast, a basal level of expression of the variant in the same sibship
indicated the existence in trans of a normal-percentage alpha-allele.
Haplotype analysis was also used in the study. This appears to be a
superb example of an isoallele affecting the expression of the phenotype
resulting from the other allele.

Autosomal dominant elliptocytosis within the same family may be
associated with transfusion-dependent hemolytic anemia in some
heterozygotes and vigorous good health in others. Motulsky et al. (1954)
conjectured that a second genetic defect, normally silent, might be the
explanation for this apparent exception to the principles of mendelian
genetics. Parquet et al. (1994) and Randon et al. (1994) showed that, in
fact, this was the case. The explanation lies in the effects on the
assembly of the alpha-spectrin and beta-spectrin chains when a
polymorphism exists at another point in the alpha-spectrin molecule
which also contains a mutation causing elliptocytosis. The beta chain is
synthesized at an early stage of assembly of the erythrocyte
cytoskeleton and binds to its attachment site (ankyrin) on the cell
membrane. Thereafter, the alpha chain floods the system and the part not
taken up into an equimolar complex by the beta chain is destroyed by
proteases in the cytosol (Moon and Lazarides, 1983). As demonstrated by
Speicher et al. (1992), the mechanism of the lateral association of the
constituent chains of the alpha-beta spectrin dimer involves strong
interactions between pairs of repeats at one end of the dimer. Randon et
al. (1994) found that it is one of these critical repeats that is
disturbed by the alpha-LELY mutation. Delaunay and Dhermy (1993), in
Lyon, France, had shown that there is a common, but low-expression and
symptomless spectrin polymorphism resulting from a substitution toward
the far end of the alpha chain; the mutation is designated as alpha-LELY
for 'low-expression allele, Lyon.' When freshly synthesized alpha chains
are assimilated by the beta chains already on the membrane, the normal
alpha chain is preferred to the mutant. With such a high frequency of
the alpha-LELY allele in the population, a third of heterozygotes
carrying an elliptocytosis mutation at the end of the spectrin alpha
chain will also possess an alpha-LELY allele. If both mutations occur in
the same alpha chain (that is to say in cis), which will be largely
rejected by the membrane-bound beta chain, it will be the normal alpha
chain that will be predominantly incorporated into the cytoskeletal
network. In this case, the polymorphism acts to rescue the double
heterozygote from the worst consequences of the hereditary
elliptocytosis. But if the mutations occur in different alpha-chain
alleles, then the normal beta-chain binding site will carry the
defective dimer binding sites onto the membrane, and the proportion of
functional spectrin tetramers will be greatly suppressed; the malign
effects of the elliptocytic mutation will be amplified. In some milder
forms of hereditary elliptocytosis, the mutation probably only weakens
rather than annihilates the association of spectrin dimers. Even in this
case (see Perrotta et al., 1994), an offspring with an elliptocytic
alpha-chain mutation together with alpha-LELY in trans is more
noticeably affected than the father with no alpha-LELY allele. (The
situation in which a polymorphism in the gene influences the expression
of the primary disease-producing mutation is observed also in the case
of the PRNP gene (176640): the asp178-to-asn mutation causes
Creutzfeldt-Jakob disease when in cis with val129 (176640.0005), whereas
it produces familial fatal insomnia when it is in cis with met129
(176640.0010).)

Randon et al. (1994) referred to the allele in cis as alpha-HE-LELY and
the diplotype in trans as alpha-HE/alpha-LELY.

Gallagher and Forget (1993) reviewed all aspects of the alpha and beta
spectrin genes in health and disease. Delaunay and Dhermy (1993)
reviewed mutations involving the spectrin heterodimer contact site which
is critical to normal self-association of spectrin. Self-association
allows the dimer to form tetramers or higher order oligomers, and
permits the whole skeleton to acquire its mechanical properties. They
referred to pyropoikilocytosis as an 'aggravated' form of
elliptocytosis. Both are defined on morphologic grounds. Hereditary
elliptocytosis shows a wide spectrum of clinical presentations, ranging
from the absence of symptoms to severe yet not life-threatening
pictures. Pyropoikilocytosis has a narrower spectrum of clinical
aspects, ranging from severe to life-threatening syndromes. They pointed
to the high incidence of so-called LE (for 'low expression') alleles of
the SPTA gene. The compound heterozygous state for an LE allele and an
HE allele (hereditary elliptocytosis) results in increased relative
expression of the latter, ending in a more severe clinical picture.
Remarkably, 4 different mutations have been found in codon 28 of SPTA1:
R28L (182860.0011), R28S (182860.0012), R28C (182860.0013), and R28H
(182860.0014). All 4 can result in severe pyropoikilocytosis if an LE
allele is present in trans. The fact that 4 mutations have been
demonstrated in codon 28 and that each of them has been found several
times suggests that the CpG dinucleotide is a hotspot for mutation.
Delaunay and Dhermy (1993) commented on the high frequency of the
leu148-dup mutation (182860.0003), also referred to as the alpha(I/65)
mutation, as well as the leu207-to-pro (182860.0016) and leu260-to-pro
(182860.0001) mutations. None of these reach as high a frequency as the
band 3 mutation accounting for Southern Asian ovalocytosis (109270.0002)
but are sufficiently frequent to raise the question of selective
advantage in relation to malaria. In vitro evidence supports this
possibility.

EVOLUTION

By database and phylogenetic analysis, Salomao et al. (2006) showed that
the SPTA1 gene is unique to mammals and that it arose through
duplication of the SPTAN1 gene (182810). They found that an SPTA1
fragment containing the site of head-to-head interaction with the
beta-chain bound more weakly than the corresponding SPTAN1 fragment, and
they identified sequences that determined the strength of the
dimer-dimer interaction on the membrane. Salomao et al. (2006) concluded
that SPTA1 is adapted for rapidly making and breaking tetramers, thus
contributing to the deformability of erythrocyte membranes.

*FIELD* AV
.0001
ELLIPTOCYTOSIS 2
SPTA1, LEU260PRO

This mutation was designated LEU254PRO by Marchesi et al. (1987) and
Sahr et al. (1989). For a time the numbering system used for SPTA1 was
based on a sequence that lacked the first 6 residues.

This substitution, which resulted from a CTG-to-CCG change in exon 6,
was found in patients with elliptocytosis (130600) by Marchesi et al.
(1987) and Sahr et al. (1989). The mutation results in a Sp-alpha I/46
variant, referring to the molecular weight of the abnormal peptide
observed after limited tryptic digestion. This variant appeared to be
restricted to the areas of the Gulf of Guinea in west Africa and to be
found in closed ethnic groups.

.0002
ELLIPTOCYTOSIS 2
SPTA1, GLN471PRO

This mutation was designated GLN465PRO by Marchesi et al. (1987) and
Sahr et al. (1989). For a time the numbering system used for SPTA1 was
based on a sequence that lacked the first 6 residues.

This substitution, which resulted from a CAG-to-CCG change in exon 11,
was found in patients with elliptocytosis (130600) by Marchesi et al.
(1987) and Sahr et al. (1989). The mutation is a Sp-alpha I/50-46b
variant.

.0003
ELLIPTOCYTOSIS 2
SPTA1, 3-BP INS, LEU154DUP

Marchesi et al. (1987) and Sahr et al. (1989) stated that the
duplication occurred after leu148, but it was later found to occur after
leu154. For a time the numbering system used for SPTA1 was based on a
sequence that lacked the first 6 residues.

This mutation has also been referred to as the alpha(I-65) mutation. In
2 American black patients with elliptocytosis (130600), Marchesi et al.
(1987) and Sahr et al. (1989) found insertion of an extra leucine
residue after leucine-148. Roux et al. (1989) identified the molecular
defect in 5 unrelated families in North Africa (Algeria) with the
alpha-spectrin form of hereditary elliptocytosis. This form of
elliptocytosis is associated with an abnormal 65-kD alpha-I peptide
(rather than the normal 80-kD) following limited trypsin digestion of
whole spectrin. The authors identified an extra leucine codon (TTG)
between codons 147 and 149 in exon 4, the coding sequence becoming CAG
TTG TTG CTG instead of CAG TTG CTG. The studies of Lecomte et al. (1988)
indicated a high prevalence of hereditary elliptocytosis due to this
mutation in populations of west Africa as well as in black people living
in North America.

Boulanger et al. (1992) described fast screening methods for detection
of this and the L260P mutation (182860.0001); the findings will be
useful in studying the relationship between malaria resistance and the
LEU154DUP mutation. Del Giudice et al. (1992) reported the same mutation
in 2 women from southern Italy, Campania and Sicily; however, the
associated haplotype was the same as that encountered in African and
American blacks and in North Africans. It is assumed that the mutation
was introduced from North Africa across the Sicilian channel and
ultimately originated from the Benin-Togo area. This was the same
migratory pathway followed by the Benin type hemoglobin S allele, which
is also present in southern Italy.

.0004
ELLIPTOCYTOSIS 2
SPTA1, SER261PRO

This mutation was designated SER255PRO by Marchesi et al. (1987) and
Sahr et al. (1989). For a time the numbering system used for SPTA1 was
based on a sequence that lacked the first 6 residues.

Marchesi et al. (1987) and Sahr et al. (1989) found this substitution,
which resulted from a TCC-to-CCC change in exon 6, in patients with
elliptocytosis (130600). This mutation is a Sp-alpha I/50-46a variant.

.0005
PYROPOIKILOCYTOSIS, HEREDITARY
ELLIPTOCYTOSIS 2, INCLUDED
SPTA1, ARG45SER

This mutation was designated ARG39SER by Lecomte et al. (1989). For a
time the numbering system used for SPTA1 was based on a sequence that
lacked the first 6 residues.

In the family of a 36-year-old man with hereditary pyropoikilocytosis
(266140), Lecomte et al. (1989) found a typical mild hereditary
elliptocytosis (130600) in the mother, 2 brothers, a sister, and 2
nieces. The proband had severe neonatal hemolytic anemia requiring
exchange transfusions and a splenectomy at 1 year of age. Lecomte et al.
(1989) demonstrated a G-to-T transversion in codon 39 (AGT for AGG),
which changed the normal arginine to a serine in alpha-spectrin. This
mutation, designated spectrin Clichy, is a Sp-alpha I/78 variant.

.0006
ELLIPTOCYTOSIS 2
SPTA1, GLY46VAL

This mutation was designated GLY40VAL by Morle et al. (1989, 1990). For
a time the numbering system used for SPTA1 was based on a sequence that
lacked the first 6 residues.

Morle et al. (1989, 1990) found this substitution in a French Caucasian
family with Sp-alpha I/74 hereditary elliptocytosis (130600) defined on
the basis of altered peptide maps following partial digestion of
spectrin. The alpha-174 kD fragment is increased at the expense of the
parent alpha-I 80 kD fragment. A GGT-to-GTT change in codon 40 (in exon
2) resulted in substitution of valine for glycine. This mutation was
designated spectrin Culoz.

.0007
ELLIPTOCYTOSIS 2
SPTA1, LEU48PHE

This mutation was designated LEU43PHE by Morle et al. (1989, 1990). For
a time the numbering system used for SPTA1 was based on a sequence that
lacked the first 6 residues.

Morle et al. (1989, 1990) found this mutation in a French Caucasian
family with Sp-alpha I/74 type of hereditary elliptocytosis (130600).
The mutation, a CTT-to-TTT change in codon 43, was demonstrated by
amplification of alpha-spectrin cDNA derived from reticulocyte mRNA.
This mutation was designated spectrin Lyon.

.0008
MOVED TO 182860.0014
.0009
SPHEROCYTOSIS, TYPE 3, AUTOSOMAL RECESSIVE
SPTA1, ALA970ASP

In the kindred with autosomal recessive spherocytosis (270970) reported
by Agre et al. (1986), Marchesi et al. (1989, 1989) identified a
CGT-to-GAT change resulting in an ala970-to-asp (A970N) substitution in
the alpha-II domain.

Boivin et al. (1993) searched for this mutation in patients with
dominant or with what the authors termed 'non-dominant' spherocytosis,
including 78 patients, 55 relatives, and 46 controls. They found that
the mutation and the HS disease gene were located on different
chromosomes and inherited independently of each other.

.0010
ELLIPTOCYTOSIS 2
SPTA1, ARG41TRP

This mutation was designated ARG35TRP by Morle et al. (1989). For a time
the numbering system used for SPTA1 was based on a sequence that lacked
the first 6 residues.

Morle et al. (1989) described spectrin Tunis, an alpha-spectrin variant
that causes asymptomatic hereditary elliptocytosis (130600) in the
heterozygous state. The variant was found in a white North African man
and his mother. Morle et al. (1989) demonstrated that a C-to-T base
substitution converted arginine-35 (CGG) to tryptophan (TGG). This
mutation is a Sp-alpha I/78 variant.

.0011
ELLIPTOCYTOSIS 2
SPTA1, ARG28LEU

In affected members of a kindred of Arab/Druze origin segregating
elliptocytosis (130600), Coetzer et al. (1991) identified a CGT-to-CTT
change resulting in substitution of leucine for arginine at codon 28 of
the SPTA1 gene. Coetzer et al. (1991) identified 3 other mutations in
codon 28 (see 182860.0012, 182860.0013, 182860.0014). All the probands
were heterozygous. All 4 point mutations abolished an AhaII restriction
enzyme site which allowed verification of linkage of the mutation with
elliptocytosis. The findings suggested that codon 28 is a hotspot for
mutations and also indicated that arginine-28 is critical for the
conformational stability and functional self-association of spectrin
heterodimers. All 4 arg28 mutations are Sp-alpha I/74 variants.

.0012
ELLIPTOCYTOSIS 2
PYROPOIKILOCYTOSIS, HEREDITARY, INCLUDED
SPTA1, ARG28SER

In affected members of 2 unrelated white kindreds of English/European
origin segregating for elliptocytosis (130600), Coetzer et al. (1991)
found a CGT-to-AGT mutation leading to substitution of serine for
arginine at codon 28 of the SPTA1 gene. See 182860.0011.

Gallagher et al. (1991) found the same mutation in a patient with
hereditary pyropoikilocytosis (266140). The patient was heterozygous for
a single structural variant of spectrin and possessed a second,
uncharacterized defect, thus explaining the difference in phenotype from
that in the patients with the same defect reported by Coetzer et al.
(1991).

.0013
ELLIPTOCYTOSIS 2
PYROPOIKILOCYTOSIS, HEREDITARY, INCLUDED
SPTA1, ARG28CYS

See 182860.0011. In affected members of 2 apparently unrelated white
kindreds from New Zealand segregating for elliptocytosis (130600),
Coetzer et al. (1991) identified a CGT-to-TGT mutation in the SPTA1 gene
that resulted in substitution of cysteine for arginine-28.

In an Italian child, Lorenzo et al. (1993) observed a de novo CGT-to-TGT
mutation at codon 28 producing severe pyropoikilocytosis (266140). The
severity of the manifestations was thought to be accounted for by the
occurrence, in trans to the alpha-28 mutation, of a polymorphism leading
to a structural abnormality of the alpha-IV/alpha-V domain junction and
with a low expression level, i.e., a so-called LE allele. The recurrent
mutation strengthens the view that codon alpha-28 is a mutational
'hotspot.'

.0014
ELLIPTOCYTOSIS 2
PYROPOIKILOCYTOSIS, HEREDITARY, INCLUDED
SPTA1, ARG28HIS

This mutation was originally reported by Garbarz et al. (1989, 1990) as
ARG22HIS (R22H). For a time the numbering system used for SPTA1 was
based on a sequence that lacked the first 6 residues.

In affected members of the French Caucasian family originally reported
by Lecomte et al. (1987), Garbarz et al. (1989, 1990) found a CAT-to-CGT
change in codon 22 in exon 2 of the SPTA1 gene (which encodes amino
acids 3 to 82 of the alpha-I domain). In the family, 12 subjects in 4
generations had a disorder of the red cells varying from mild
elliptocytosis to hemolytic elliptocytosis (130600) to
pyropoikilocytosis (266140). In 8 of the 12 affected persons,
heterozygosity for a spectrin alpha-I/74 kD defect was demonstrated by
analysis of spectrin tryptic fragments. The defect resulted in decreased
ability of the spectrin dimers to self-associate. Clinical severity
correlated with amount of mutant spectrin and excess of spectrin dimer
in the red cell membrane.

The R28H mutation was found by Baklouti et al. (1991) in a boy with
severe elliptopoikilocytosis and in his clinically normal father. The
severe expression in the son was attributable to the existence in trans
of the alpha-V/41 polymorphism transmitted from the mother.

In an American black kindred and a black kindred from Ghana, Coetzer et
al. (1991) identified a CGT-to-CAT mutation that resulted in
substitution of histidine for arginine-28. See 182860.0011.

.0016
PYROPOIKILOCYTOSIS, HEREDITARY
ELLIPTOCYTOSIS 2, INCLUDED
SPTA1, LEU207PRO

In 9 individuals from 5 unrelated families with hereditary
elliptocytosis (130600) or hereditary pyropoikilocytosis (266140),
including one of the original HPP probands reported by Zarkowsky et al.
(1975), Gallagher et al. (1992) found the alpha-I/46-50a peptide after
limited tryptic digestion of spectrin. Further studies identified a
point mutation causing the replacement of a highly conserved leucine
residue by proline at position 207 in the alpha-spectrin chain, a site
51 residues to the amino-terminal side of the abnormal proteolytic
cleavage site. Dalla Venezia et al. (1993) found the leu207-to-pro
mutation in a Moroccan family in both homozygous and heterozygous
states. The mutated allele carried, in cis, the common alpha-V/41
polymorphism, which is associated with a low expression level. Dalla
Venezia et al. (1993) suggested that the cis combination of an HE
mutation and the alpha-V/41 polymorphism accounts for the low expression
of the abnormal allele in the heterozygous state.

In the original family of Zarkowsky et al. (1975), the L207P mutation
was in compound heterozygous state with an SPTA1 allele associated with
a defect in alpha-spectrin production. By analysis of reticulocyte
alpha-spectrin cDNA from 1 of the original HPP patients, Costa et al.
(2005) identified a G-to-A transition (182860.0024) at position +5 of
the donor splice site of intron 22 of the SPTA1 gene, resulting in
insertion of intronic fragments and an in-frame premature termination
codon. Following gene transfer of the IVS22+5 mutation into tissue
culture cells, there was complete absence of normally spliced SPTA1 gene
transcript.

.0017
PYROPOIKILOCYTOSIS, HEREDITARY
SPTA1, LYS48ARG

In a case of hereditary pyropoikilocytosis (266140), Gallagher et al.
(1991) found substitution of arginine for lysine at residue 48 of
alpha-spectrin. HPP is a severe hemolytic anemia characterized by
abnormal sensitivity of red blood cells to heat and erythrocyte
morphology similar to that seen in thermal burns. The genetics of HPP
usually falls into 1 of 3 categories: (1) the patients may be homozygous
for a structural variant of spectrin; (2) they may be compound
heterozygous for 2 different structural variants of spectrin; or (3)
they may be heterozygous for a single structural variant of spectrin and
possess a second, uncharacterized defect. The patient with the
lys48-to-arg mutation was of the third type. This mutation is a Sp-alpha
I/74 variant.

.0018
ELLIPTOCYTOSIS 2
SPTA1, ASP791GLU

Alloisio et al. (1992) found an alpha-spectrin variant associated in the
heterozygous state with asymptomatic elliptocytosis (130600) and a
minimal defect in spectrin dimer self-association in a Tunisian family.
The responsible mutation was found to be a GAC-to-GAA transversion
resulting in substitution of glutamic acid for aspartic acid at codon
791. As in most alpha-spectrin variants associated with elliptocytosis,
the change altered helix 3 of the proposed triple helical model of
spectrin structure. This change was the most distant from the N terminus
of alpha-spectrin yet found in variants associated with elliptocytosis.
This mutation, designated spectrin Jendouba, is a Sp-alpha II/31
variant.

.0019
ELLIPTOCYTOSIS 2
SPTA1, IVS17, G-A, -1

In an Algerian family, Alloisio et al. (1988) identified a new
alpha-spectrin variant, spectrin Oran, that in the homozygous state
caused severe elliptocytosis (130600). All but 2 obligate heterozygotes
were clinically normal and had normal hematologic findings; one of the
exceptions 'presented some degree of anisocytosis with rare
elliptocytes' and the other had findings consistent with heterozygosity
for a form of alpha-thalassemia affecting 10% of Algerian people. As
indicated in the report of Alloisio et al. (1993), several members of
the family who were homozygotes required transfusion, and partial
splenectomy was performed at the age of 8 months in 1 of these. Alloisio
et al. (1993) demonstrated loss of amino acids 822 to 862 (helix 2 of
repeating segment alpha-8). The ultimate genetic lesion was found to be
a G-to-A transition at intronic position -1 in the acceptor splice site
of intron 17 resulting in skipping of exon 18. The substitution also
created an acceptor splice site 1 basepair downstream, but the latter
was used only to a minor extent. This mutation is a Sp-alpha II/21
variant.

.0020
ELLIPTOCYTOSIS 2
PYROPOIKILOCYTOSIS, INCLUDED
SPTA1, EX5DEL, SVA RETROTRANSPOSON INS

In a 3-generation family with hereditary elliptocytosis (130600) and
pyropoikilocytosis (266140), Hassoun et al. (1994) found a truncated
alpha-spectrin protein. They showed, furthermore, that the SPTA1 gene
had been disrupted by a mobile element resulting in exon skipping. The
element caused duplication of the insertion site and was terminated by a
long poly(A) tail downstream of multiple consensus polyadenylation
signals. Southern blot analysis of human genomic DNA, using this element
as probe, revealed 1 to 3 copies per individual. The element had no
homology to any previously reported sequence and therefore appeared to
be a member of a novel family of mobile elements. This mutation is a
Sp-alpha I/50-46a variant.

Ostertag et al. (2003) showed that the sequence change observed by
Hassoun et al. (1994) was the result of an SVA-mediated transduction
event. (Shen et al. (1994) used the term 'SVA' (SINE-R, VNTR, and alu)
to describe such a 'composite retroposon.') Ostertag et al. (2003)
showed that the de novo insertion into the alpha-spectrin gene was
caused by an SVA-mediated transduction.

.0021
PYROPOIKILOCYTOSIS, HEREDITARY
ELLIPTOCYTOSIS 2, INCLUDED
SPTA1, IVS19, T-G, -13

Lecomte et al. (1990) reported the case of a patient with severe
poikilocytic anemia, the child of apparently unrelated parents, both
from Guadeloupe in the French West Indies. The baby had severe hemolytic
anemia requiring frequent blood transfusions. Partial splenectomy was
performed at age 3, but complete splenectomy was necessary 2 years
later. Thereafter the propositus experienced a compensated hemolysis.
Blood smears showed marked poikilocytosis with spherocytes,
microspherocytes, and a few elliptocytes as observed in hereditary
pyropoikilocytosis (266140). In the patient reported by Lecomte et al.
(1990), Fournier et al. (1997) identified a splicing mutation of the
SPTA1 gene: a T-to-G transversion at nucleotide position -13 upstream of
the 3-prime acceptor splice site of exon 20. This polypyrimidine tract
mutation created a new acceptor site, AT-to-AG, and led to the
production of 2 novel mRNAs. One mRNA contained a 12-nucleotide intronic
insertion upstream of exon 20. This insertion introduced a termination
codon into the reading frame and was predicted to encode a truncated
protein that lacked the nucleation site and thus could not be assembled
in the membrane. In the other mRNA, there was in-frame skipping of exon
20, predicting a truncated alpha-spectrin chain. The homozygous
propositus had only truncated (277 kD) alpha-spectrin chains in his
erythrocyte membranes. His heterozygous parents were clinically and
biochemically normal. This allele was identified in 3% of asymptomatic
individuals from Benin, Africa, when a new MwoI restriction site was
used for identification of heterozygosity. This mutation, designated
spectrin St Claude, is a Sp-alpha II/47 variant.

Burke et al. (1998) found the same mutation in the SPTA1 gene in a South
African hereditary elliptocytosis (130600) family and referred to it as
spectrin Johannesburg. The kindred was of Afrikaner origin. Although the
parents were apparently unrelated, the probands were homozygous. Partial
spectrin deficiency in the proband's erythrocyte membranes resulted from
the spectrin-ankyrin binding defect and destabilized the lipid bilayer,
causing spherocytes. The reduced membrane spectrin content in concert
with the milder dimer self-association defect further weakened the
membrane skeleton and allowed deformation of the erythrocytes into
elliptocytes and poikilocytes. The observations illustrated how a single
point mutation in the alpha-spectrin gene impairs functions of both the
alpha- and the beta-spectrin proteins, resulting in qualitative and
quantitative membrane abnormalities.

.0022
SPHEROCYTOSIS, TYPE 3, DUE TO SPECTRIN PRAGUE
SPTA1, IVS36, A-G, -1

Wichterle et al. (1996) studied a patient with severe spherocytic
hemolytic anemia (270970) without a family history of spherocytosis.
Analysis of the patient's erythrocyte membrane proteins revealed
spectrin deficiency and a truncated alpha-spectrin protein. They
determined that the patient was a compound heterozygote with 2 mutations
in the alpha-spectrin gene. The mutation in the paternal allele,
designated alpha-spectrin-Prague, was an A-to-G transition in the
penultimate position of intron 36 that led to skipping of exon 37,
frameshift, and production of the truncated alpha-spectrin protein. The
maternal allele, designated alpha-spectrin-Lepra, contained a C-to-T
transition at position -99 of intron 30 (182860.0023). This mutation
enhanced an alternative acceptor splice site 70 nucleotides upstream
from the regular site. The alternative splicing caused a frameshift and
premature termination of translation leading to a significant decrease
in alpha-spectrin production. The spectrin-Lepra mutation was linked to
a spectrin alpha-IIa marker that was found to be associated with
recessive or nondominant spectrin-deficient hereditary spherocytosis in
approximately 50% of studied families. Wichterle et al. (1996) concluded
that the spectrin-Lepra mutation combined in trans with the alpha-Prague
mutation was responsible for the severe hemolytic anemia in the proband.
They suggested, furthermore, that the spectrin-Lepra allele may
frequently be involved in the pathogenesis of recessive or nondominant
spectrin-deficient hereditary spherocytosis.

.0023
SPHEROCYTOSIS, TYPE 3, DUE TO SPECTRIN LEPRA
SPTA1, IVS30, C-T, -99

See 182860.0022 and Wichterle et al. (1996).

.0024
PYROPOIKILOCYTOSIS, HEREDITARY
SPTA1, IVS22DS, G-A, +5

See 182860.0016 and Costa et al. (2005).

*FIELD* SA
Coetzer and Zail (1982); Coetzer and Zail (1981); Evans et al. (1983);
Garbarz et al. (1986); Lane et al. (1987); Lecomte et al. (1985);
Linnenbach et al. (1986); Liu et al. (1982); Morle et al. (1988);
Morle et al. (1989); Palek and Coetzer (1987)
*FIELD* RF
1. Agre, P.; Asimos, A.; Casella, J. F.; McMillan, C.: Inheritance
pattern and clinical response to splenectomy as a reflection of erythrocyte
spectrin deficiency in hereditary spherocytosis. New Eng. J. Med. 315:
1579-1583, 1986.

2. Alloisio, N.; Guetarni, D.; Morle, L.; Pothier, B.; Ducluzeau,
M. T.; Soun, A.; Colonna, P.; Clerc, M.; Philippe, N.; Delaunay, J.
: SP-alpha(I/65) hereditary elliptocytosis in North Africa. Am. J.
Hemat. 23: 113-122, 1986.

3. Alloisio, N.; Morle, L.; Pothier, B.; Roux, A.-F.; Marechal, J.;
Ducluzeau, M.-T.; Benhadji-Zouaoui, Z.; Delaunay, J.: Spectrin Oran
(alpha II/21), a new spectrin variant concerning the alpha II domain
and causing severe elliptocytosis in the homozygous state. Blood 71:
1039-1047, 1988.

4. Alloisio, N.; Wilmotte, R.; Marechal, J.; Texier, P.; Denoroy,
L.; Feo, C.; Benhadji-Zouaoui, Z.; Delaunay, J.: A splice site mutation
of alpha-spectrin gene causing skipping of exon 18 in hereditary elliptocytosis. Blood 81:
2791-2798, 1993.

5. Alloisio, N.; Wilmotte, R.; Morle, L.; Baklouti, F.; Marechal,
J.; Ducluzeau, M.-T.; Denoroy, L.; Feo, C.; Forget, B. G.; Kastally,
R.; Delaunay, J.: Spectrin Jendouba: an alpha-II/31 spectrin variant
that is associated with elliptocytosis and carries a mutation distant
from the dimer self-association site. Blood 80: 809-815, 1992.

6. Baklouti, F.; Marechal, J.; Morle, L.; Alloisio, N.; Wilmotte,
R.; Pothier, B.; Ducluzeau, M.-T.; Kastally, R.; Delaunay, J.: Occurrence
of the alpha-I 22 arg-to-his (CGT-to-CAT) spectrin mutation in Tunisia:
potential association with severe elliptopoikilocytosis. Brit. J.
Haemat. 78: 108-113, 1991.

7. Birkenmeier, C. S.; McFarland-Starr, E. C.; Barker, J. E.: Chromosomal
location of three spectrin genes: relationship to the inherited hemolytic
anemias of mouse and man. Proc. Nat. Acad. Sci. 85: 8121-8125, 1988.

8. Boivin, P.; Galand, C.; Devaux, I.; Lecomte, C.; Garbarz, M.; Dhermy,
D.: Spectrin alpha-IIa variant in dominant and nondominant spherocytosis. Hum.
Genet. 92: 153-156, 1993. Note: Erratum: Hum. Genet. 93: 614 only,
1994.

9. Boulanger, L.; LeCompte, M.-C.; Dhermy, D.; Garbarz, M.: Fast
screening methods to detect mutations of spectrin in subjects with
hereditary elliptocytosis. (Letter) Am. J. Hum. Genet. 51: 440-442,
1992.

10. Burke, J. P. W. G.; Van Zyl, D.; Zail, S. S.; Coetzer, T. L.:
Reduced spectrin-ankyrin binding in a South African hereditary elliptocytosis
kindred homozygous for spectrin St Claude. (Letter) Blood 92: 2591-2592,
1998.

11. Coetzer, T.; Zail, S.: Spectrin tetramer-dimer equilibrium in
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12. Coetzer, T.; Zail, S. S.: Tryptic digestion of spectrin in variants
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13. Coetzer, T. L.; Sahr, K.; Prchal, J.; Blacklock, H.; Peterson,
L.; Koler, R.; Doyle, J.; Manaster, J.; Palek, J.: Four different
mutations in codon 28 of alpha spectrin are associated with structurally
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Clin. Invest. 88: 743-749, 1991.

14. Costa, D. B.; Lozovatsky, L.; Gallagher, P. G.; Forget, B. G.
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15. Dalla Venezia, N.; Wilmotte, R.; Morle, L.; Forissier, A.; Parquet,
N.; Garbarz, M.; Rousset, T.; Dhermy, D.; Alloisio, N.; Delaunay,
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16. Delaunay, J.; Dhermy, D.: Mutations involving the spectrin heterodimer
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17. del Giudice, E. M.; Ducluzeau, M. T.; Alloisio, N.; Wilmotte,
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hereditary elliptocytosis in southern Italy: evidence for an African
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18. Evans, J. P. M.; Baines, A. J.; Hann, I. M.; Al-Hakim, I.; Knowles,
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19. Fournier, C. M.; Nicolas, G.; Gallagher, P. G.; Dhermy, D.; Grandchamp,
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20. Gallagher, P. G.; Forget, B. G.: Spectrin genes in health and
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23. Gallagher, P. G.; Tse, W. T.; Coetzer, T.; Lecomte, M.-C.; Garbarz,
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J.; Forget, B. G.: A common type of the spectrin alpha-I 46-50a-kD
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24. Gallagher, P. G.; Tse, W. T.; Marchesi, S. L.; Zarkowsky, H. S.;
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25. Garbarz, M.; Lecomte, M.-C.; Feo, C.; Devaux, I.; Picat, C.; Lefebvre,
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26. Garbarz, M.; Lecomte, M. C.; Dhermy, D.; Feo, C.; Chaveroche,
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27. Garbarz, M.; Lecomte, M. C.; Lefebvre, C.; Devaux, I.; Galibert,
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28. Guetarni, D.; Roux, A.-F.; Alloisio, N.; Morle, F.; Ducluzeau,
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29. Hassoun, H.; Coetzer, T. L.; Vassiliadis, J. N.; Sahr, K. E.;
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30. Huebner, K.; Palumbo, A. P.; Isobe, M.; Kozak, C. A.; Monaco,
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1985.

31. Iarocci, T. A.; Wagner, G. M.; Mohandas, N.; Lane, P. A.; Mentzer,
W. C.: Hereditary poikilocytic anemia associated with the co-inheritance
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32. Keats, B. J. B.: Another elliptocytosis locus on chromosome 1? Hum.
Genet. 50: 227-230, 1979.

33. Knowles, W. J.; Bologna, M. L.; Chasis, J. A.; Marchesi, S. L.;
Marchesi, V. T.: Common structural polymorphisms in human erythrocyte
spectrin. J. Clin. Invest. 73: 973-979, 1984.

34. Kotula, L.; Laury-Kleintop, L. D.; Showe, L.; Sahr, K.; Linnenbach,
A. J.; Forget, B.; Curtis, P. J.: The exon-intron organization of
the human erythrocyte alpha-spectrin gene. Genomics 9: 131-140,
1991.

35. Lane, P. A.; Shew, R. L.; Iarocci, T. A.; Mohandas, N.; Hays,
T.; Mentzer, W. C.: Unique alpha-spectrin mutant in a kindred with
common hereditary elliptocytosis. J. Clin. Invest. 79: 989-996,
1987.

36. Lawler, J.; Coetzer, T. L.; Mankad, V. N.; Moore, R. B.; Prchal,
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37. Lawler, J.; Coetzer, T. L.; Palek, J.; Jacob, H. S.; Luban, N.
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38. Lawler, J.; Liu, S.-C.; Palek, J.; Prchal, J.: A molecular defect
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39. Lecomte, M.-C.; Dhermy, D.; Garbarz, M.; Feo, C.; Gautero, H.;
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40. Lecomte, M.-C.; Dhermy, D.; Solis, C.; Ester, A.; Feo, C.; Gautero,
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41. Lecomte, M.-C.; Garbarz, M.; Grandchamp, B.; Feo, C.; Gautero,
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42. Lecomte, M. C.; Dhermy, D.; Garbarz, M.; Feo, C.; Gautero, H.;
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43. Lecomte, M. C.; Dhermy, D.; Gautero, H.; Bournier, O.; Galand,
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45. Linnenbach, A. J.; Speicher, D. W.; Marchesi, V. T.; Forget, B.
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46. Liu, S. C.; Palek, J.; Prchal, J. T.: Defective spectrin dimer-dimer
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47. Lorenzo, F.; del Giudice, E. M.; Alloisio, N.; Morle, L.; Forissier,
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48. Marchesi, S. L.; Agre, P. A.; Speicher, D. W.; Tse, W. T.; Forget,
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52. Middleton-Price, H.; Gendler, S.; Malcolm, S.: Close linkage
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54. Morle, L.; Alloisio, N.; Ducluzeau, M. T.; Pothier, B.; Bilbech,
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55. Morle, L.; Morle, F.; Roux, A. F.; Godet, J.; Forget, B. G.; Denoroy,
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56. Morle, L.; Roux, A.-F.; Alloisio, N.; Pothier, B.; Starck, J.;
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Sci. 103: 643-648, 2006.

72. Shen, L.; Wu, L. C.; Sanlioglu, S.; Chen, R.; Mendoza, A. R.;
Dangel, A. W.; Carroll, M. C.; Zipf, W. B.; Yu, C. Y.: Structure
and genetics of the partially duplicated gene RP located immediately
upstream of the complement C4A and the C4B genes in the HLA class
III region: molecular cloning, exon-intron structure, composite retroposon,
and breakpoint of gene duplication. J. Biol. Chem. 269: 8466-8476,
1994.

73. Speicher, D. W.; Marchesi, V. T.: Erythrocyte spectrin is comprised
of many homologous triple helical segments. Nature 311: 177-180,
1984.

74. Speicher, D. W.; Weglarz, L.; DeSilva, T. M.: Properties of human
red cell spectrin heterodimer (side-to-side) assembly and identification
of an essential nucleation site. J. Biol. Chem. 267: 14775-14782,
1992.

75. Wichterle, H.; Hanspal, M.; Palek, J.; Jarolim, P.: Combination
of two mutant alpha spectrin alleles underlies a severe spherocytic
hemolytic anemia. J. Clin. Invest. 98: 2300-2307, 1996.

76. Zarkowsky, H. S.; Mohandas, N.; Speaker, C. B.; Shohet, S. B.
: A congenital haemolytic anaemia with thermal sensitivity of the
erythrocyte membrane. Brit. J. Haemat. 29: 537-543, 1975.

*FIELD* CN
Carol A. Bocchini - updated: 2/19/2009
Victor A. McKusick - updated: 2/8/2007
Victor A. McKusick - updated: 6/20/2006
Patricia A. Hartz - updated: 3/10/2006
Victor A. McKusick - updated: 1/5/2004
Victor A. McKusick - updated: 3/2/1999
Victor A. McKusick - updated: 2/27/1999
Victor A. McKusick - updated: 11/13/1998
Victor A. McKusick - updated: 9/3/1997
Victor A. McKusick - updated: 5/16/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
mgross: 12/21/2010
terry: 3/19/2009
carol: 3/18/2009
carol: 2/26/2009
carol: 2/19/2009
carol: 2/18/2009
terry: 2/8/2007
wwang: 6/20/2006
terry: 6/20/2006
wwang: 3/31/2006
wwang: 3/24/2006
terry: 3/10/2006
alopez: 2/3/2006
mgross: 3/17/2004
cwells: 1/6/2004
terry: 1/5/2004
terry: 6/11/1999
carol: 3/7/1999
terry: 3/2/1999
terry: 3/1/1999
carol: 2/27/1999
carol: 11/13/1998
terry: 11/13/1998
dkim: 9/11/1998
dkim: 7/21/1998
terry: 6/17/1998
terry: 6/3/1998
alopez: 5/15/1998
terry: 9/8/1997
terry: 9/3/1997
terry: 6/2/1997
alopez: 5/20/1997
terry: 5/16/1997
mark: 8/15/1996
mark: 5/28/1996
terry: 5/22/1996
terry: 2/6/1995
carol: 1/24/1995
warfield: 4/14/1994
mimadm: 3/13/1994
carol: 10/19/1993
carol: 6/29/1993

MIM 266140
*RECORD*
*FIELD* NO
266140
*FIELD* TI
#266140 PYROPOIKILOCYTOSIS, HEREDITARY; HPP
*FIELD* TX
A number sign (#) is used with this entry because hereditary
read morepyropoikilocytosis can be caused by mutation in the alpha-spectrin
(182860) or the beta-spectrin gene (182870).

DESCRIPTION

Hereditary pyropoikilocytosis was originally described by Zarkowsky et
al. (1975) as a distinct hemolytic anemia characterized by
microspherocytosis, poikilocytosis, and an unusual thermal sensitivity
of red cells.

HPP is a subset of hereditary elliptocytosis (see 611804) due to
homozygous or compound heterozygous mutations in spectrin leading to
severe disruption of spectrin self-association (review by An and
Mohandas, 2008).

CLINICAL FEATURES

Liu et al. (1981) studied 2 patients from unrelated black families. Both
had a history of hemolytic anemia since birth (Palek et al., 1981).
Spectrin from the abnormal cells has an increased susceptibility to
thermal denaturation (Chang et al., 1979). Liu et al. (1981) concluded
that self-association of spectrin dimers into tetramers is defective,
thus accounting for the instability of red cell membrane skeletons. The
asymptomatic mothers, presumed heterozygotes, showed a mild but
reproducible increase of spectrin dimers in 0 degree C extracts and a
defective reassociation of spectrin dimers to tetramers both in solution
and in the membrane. The mothers showed normal red cell morphology and
thermal stability.

Mallouh et al. (1984) reported Saudi brother and sister with HPP. Both
parents and 8 sibs had normal red cells; 3 sibs had elliptocytosis on
peripheral blood smears.

Lecomte et al. (1987) described a Caucasian kindred in which a woman and
2 of her maternal uncles had HPP with severe hemolytic anemia, whereas
her mother and daughter had mild hereditary elliptocytosis. The
proposita's father was clinically and hematologically normal and had no
abnormality of red cell membranes. A defect in alpha-spectrin was found
in all 5 individuals. The reason for the phenotypic differences was not
clear.

MOLECULAR GENETICS

Gallagher et al. (1992) demonstrated that one of the original HPP
probands reported by Zarkowsky et al. (1975) had a substitution of
proline for leucine at position 207 of the alpha-spectrin chain (L207P;
182860.0016). By analysis of reticulocyte alpha-spectrin cDNA from one
of the HPP patients reported by Zarkowsky et al. (1975), Costa et al.
(2005) demonstrated that the non-L207P allele had a G-to-A transition at
position +5 of the donor splice site of intron 22 of the SPTA1 gene
(182860.0024).

In affected members of 2 families segregating HPP, Sahr et al. (1993)
identified homozygosity for a mutation in the SPTB gene (182870.0008).

*FIELD* SA
Knowles et al. (1983); Lawler et al. (1982); Prchal et al. (1982)
*FIELD* RF
1. An, X.; Mohandas, N.: Disorders of red cell membrane. Brit. J.
Haemat. 141: 367-375, 2008.

2. Chang, K.; Williamson, J. R.; Zarkowsky, H. S.: Effect of heat
on the circular dichroism of spectrin in hereditary pyropoikilocytosis. J.
Clin. Invest. 64: 326-328, 1979.

3. Costa, D. B.; Lozovatsky, L.; Gallagher, P. G.; Forget, B. G.:
A novel splicing mutation of the alpha-spectrin gene in the original
hereditary pyropoikilocytosis kindred. Blood 106: 4367-4369, 2005.

4. Gallagher, P. G.; Tse, W. T.; Coetzer, T.; Lecomte, M.-C.; Garbarz,
M.; Zarkowsky, H. S.; Baruchel, A.; Ballas, S. K.; Dhermy, D.; Palek,
J.; Forget, B. G.: A common type of the spectrin alpha-I 46-50a-kD
peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis
is associated with a mutation distant from the proteolytic cleavage
site: evidence for the functional importance of the triple helical
model of spectrin. J. Clin. Invest. 89: 892-898, 1992.

5. Knowles, W. J.; Morrow, J. S.; Speicher, D. W.; Zarkowsky, H. S.;
Mohandas, N.; Mentzer, W. C.; Shohet, S. B.; Marchesi, V. T.: Molecular
and functional changes in spectrin from patients with hereditary pyropoikilocytosis. J.
Clin. Invest. 71: 1867-1877, 1983.

6. Lawler, J.; Liu, S.-C.; Palek, J.; Prchal, J.: Molecular defect
of spectrin in hereditary pyropoikilocytosis: alterations in the trypsin-resistant
domain involved in spectrin self-association. J. Clin. Invest. 70:
1019-1030, 1982.

7. Lecomte, M. C.; Dhermy, D.; Garbarz, M.; Feo, C.; Gautero, H.;
Bournier, O.; Picat, C.; Chaveroche, I.; Galand, C.; Boivin, P.:
Hereditary pyropoikilocytosis and elliptocytosis in a Caucasian family:
transmission of the same molecular defect in spectrin through three
generations with different clinical expression. Hum. Genet. 77:
329-334, 1987.

8. Liu, S.-C.; Palek, J.; Prchal, J.; Castleberry, R. P.: Altered
spectrin dimer-dimer association and instability of erythrocyte membrane
skeletons in hereditary pyropoikilocytosis. J. Clin. Invest. 68:
597-605, 1981.

9. Mallouh, A.; Sa'di, A. R.; Ahmad, M. S.; Salamah, M.: Hereditary
pyropoikilocytosis: report of two cases from Saudi Arabia. Am. J.
Med. Genet. 18: 413-417, 1984.

10. Palek, J.; Liu, S. C.; Liu, P. A.; Prchal, J.; Castleberry, R.
P.: Altered assembly of spectrin in red cell membranes in hereditary
pyropoikilocytosis. Blood 57: 130-139, 1981.

11. Prchal, J.; Castleberry, R. P.; Parmley, R. T.; Crist, W. M.;
Mallouh, A.: Hereditary pyropoikilocytosis and elliptocytosis; clinical,
laboratory and ultrastructural features in infants and children. Pediat.
Res. 16: 484-489, 1982.

12. Sahr, K. E.; Coetzer, T. L.; Moy, L. S.; Derick, L. H.; Chishti,
A. H.; Jarolim, P.; Lorenzo, F.; del Giudice, E. M.; Iolascon, A.;
Gallanello, R.; Cao, A.; Delaunay, J.; Liu, S.-C.; Palek, J.: Spectrin
Cagliari: an ala-to-gly substitution in helix 1 of beta-spectrin repeat
17 that severely disrupts the structure and self-association of the
erythrocyte spectrin heterodimer. J. Biol. Chem. 268: 22656-22662,
1993.

13. Zarkowsky, H. S.; Mohandas, N.; Speaker, C. B.; Shohet, S. B.
: A congenital haemolytic anaemia with thermal sensitivity of the
erythrocyte membrane. Brit. J. Haemat. 29: 537-543, 1975.

*FIELD* CS

Heme:
Pyropoikilocytosis;
Hemolytic anemia;
Microspherocytosis;
Poikilocytosis;
Elliptocytosis

Lab:
Red cell thermal sensitivity;
Increased susceptibility of spectrin to thermal denaturation

Inheritance:
Autosomal recessive

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 03/19/2009
carol: 3/19/2009
carol: 3/18/2009
carol: 2/18/2009
mimadm: 3/12/1994
carol: 12/16/1993
carol: 10/13/1992
carol: 5/4/1992
supermim: 3/17/1992
carol: 2/7/1992

MIM 270970
*RECORD*
*FIELD* NO
270970
*FIELD* TI
#270970 SPHEROCYTOSIS, TYPE 3; SPH3
;;SPHEROCYTOSIS, HEREDITARY, 3; HS3
*FIELD* TX
read moreA number sign (#) is used with this entry because hereditary
spherocytosis-3 is caused by mutation in the alpha-spectrin gene (SPTA;
182860) on chromosome 1q21.

For a general description and a discussion of heterogeneity of
spherocytosis, see 182900.

CLINICAL FEATURES

Agre et al. (1982) reported 2 daughters, of related but normal parents,
who had nearly fatal hemolytic anemia requiring early splenectomy. Both
improved strikingly thereafter but spherocytosis persisted. Red cell
membranes were at least 50% deficient in spectrin, with band 1 reduced
more than band 2. No defect was found in membrane binding of spectrin or
in membrane binding sites (ankyrin). The parents were fourth cousins.
Parentage was confirmed by HLA typing. Extensive hematologic studies
showed no abnormality in the parents and other close relatives. Agre et
al. (1986) found that distally related homozygotes showed different
clinical severities and different spectrin levels as determined by
radioimmunoassay.

Agre et al. (1985) demonstrated deficiency of red cell spectrin in cases
of several different types of spherocytosis. A number of observations
indicated that deficiency of spectrin is a primary factor in the
pathogenesis of spherocytosis. Studies in both mice and men indicated
that a variety of mutations affecting spectrin synthesis or stability
can underlie spherocytosis.

Agre et al. (1986) found that spectrin levels in all patients with
spherocytosis were inversely related to osmotic fragility and were also
correlated with the clinical response to splenectomy.

INHERITANCE

In the patients with spherocytosis reported by Agre et al. (1982),
inheritance was autosomal recessive.

MOLECULAR GENETICS

In the kindred with autosomal recessive spherocytosis reported by Agre
et al. (1986), Marchesi et al. (1989, 1989) identified a missense
mutation in the alpha-II domain of the SPTA gene (182860.0005).

In a patient with severe spherocytic hemolytic anemia, Wichterle et al.
(1996) identified compound heterozygosity for 2 mutations in the SPTA
gene (182860.0022; 182860.0023).

ANIMAL MODEL

A morphologically comparable disorder in the deer mouse Peromyscus is
inherited as a recessive (Anderson et al., 1960). The defect in
autosomal recessive spherocytosis of the laboratory mouse is a
deficiency of spectrin (Greenquist et al., 1978; Shohet, 1979). The
homozygous mice have less than 50% of the normal amount of spectrin and
heterozygotes have normal levels of spectrin. That the defect resides in
alpha-spectrin is indicated by the close linkage of the spherocytosis
and alpha-spectrin genes on chromosome 1 (Birkenmeier et al., 1988).

*FIELD* SA
Bodine et al. (1984); Unger et al. (1983)
*FIELD* RF
1. Agre, P.; Asimos, A.; Casella, J. F.; McMillan, C.: Inheritance
pattern and clinical response to splenectomy as a reflection of erythrocyte
spectrin deficiency in hereditary spherocytosis. New Eng. J. Med. 315:
1579-1583, 1986.

2. Agre, P.; Casella, J. F.; Zinkham, W. H.; McMillan, C.; Bennett,
V.: Partial deficiency of erythrocyte spectrin in hereditary spherocytosis. Nature 314:
380-383, 1985.

3. Agre, P.; Orringer, E. P.; Bennett, V.: Deficient red cell spectrin
in severe, recessively inherited spherocytosis. New Eng. J. Med. 306:
1155-1161, 1982.

4. Anderson, R.; Huestis, R. R.; Motulsky, A. G.: Hereditary spherocytosis
in the deer mouse: its similarity to the human disease. Blood 15:
491-504, 1960.

5. Birkenmeier, C. S.; McFarland-Starr, E. C.; Barker, J. E.: Chromosomal
location of three spectrin genes: relationship to the inherited hemolytic
anemias of mouse and man. Proc. Nat. Acad. Sci. 85: 8121-8125, 1988.

6. Bodine, D. M., IV; Birkenmeier, C. S.; Barker, J. E.: Spectrin
deficient inherited hemolytic anemias in the mouse: characterization
by spectrin synthesis and mRNA activity in reticulocytes. Cell 37:
721-729, 1984.

7. Greenquist, A. C.; Shohet, S. B.; Bernstein, S. E.: Marked reduction
of spectrin in hereditary spherocytosis in the common house mouse. Blood 51:
1149-1155, 1978.

8. Marchesi, S. L.; Agre, P. A.; Speicher, D. W.; Tse, W. T.; Forget,
B. G.: Mutant spectrin alpha-II domain in recessively inherited spherocytosis. Blood Suppl.
1: 682 only, 1989.

9. Marchesi, S. L.; Agre, P. A.; Speicher, D. W.; Tse, W. T.; Forget,
B. G.: Mutant spectrin alpha-II domain in recessively inherited spherocytosis.
(Abstract) Blood 74: 182A, 1989.

10. Shohet, S. B.: Reconstitution of spectrin-deficient spherocytic
mouse erythrocyte membranes. J. Clin. Invest. 64: 483-494, 1979.

11. Unger, A. E.; Harris, M. J.; Bernstein, S. E.; Falcone, J. C.;
Lux, S. E.: Hemolytic anemia in the mouse: report of a new mutation
and clarification of its genetics. J. Hered. 74: 88-92, 1983.

12. Wichterle, H.; Hanspal, M.; Palek, J.; Jarolim, P.: Combination
of two mutant alpha spectrin alleles underlies a severe spherocytic
hemolytic anemia. J. Clin. Invest. 98: 2300-2307, 1996.

*FIELD* CS

Heme:
Severe hemolytic anemia;
Spherocytosis

Lab:
Red cell membranes deficient in spectrin with band 1 reduced more
than band 2;
Normal spectrin membrane binding and binding sites (ankyrin)

Inheritance:
Autosomal recessive

*FIELD* CN
Carol A. Bocchini - updated: 2/26/2009

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 08/19/2009
carol: 2/26/2009
mimadm: 3/12/1994
supermim: 3/17/1992
carol: 3/2/1992
carol: 1/30/1992
supermim: 3/20/1990
supermim: 2/8/1990

RBCC Red Blood Cell Collection

Full text data of SPTA1