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Gene Mapping and Medical Genetics Molecular Genetics of Human

Gene Mapping and Medical Genetics Molecular Genetics of Human

J Med Genet: first published as 10.1136/jmg.23.3.193 on 1 June 1986. Downloaded from mapping and medical genetics

Journal of Medical Genetics 1986, 23, 193-199 of 4

JAMES A GUSELLA, T CONRAD GILLIAM, MARCY E MACDONALD, SHIRLEY V CHENG, AND RUDOLPH E TANZI From the Neurogenetics Laboratory, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA.

SUMMARY The recent discovery that the gene causing Huntington's (HD) resides on has generated increased interest in this . Chromosome 4 contains two of the more informative conventional genetic markers, GC and MNS, but most loci have been assigned to it by recombinant DNA techniques. There are currently more anonymous DNA fragments detecting restriction fragment length polymorphisms (RFLPs) on chromosome 4 than on any other autosome. In addition, most of the cloned from this chromosome detect useful

RFLPs. A map including both conventional and DNA markers should soon span copyright. the entire chromosome and will undoubtedly lead to the localisation of other inherited disorders.

Chromosome 4 comprises 6 5 00 of human genomic constructed. This development will set the stage for DNA and therefore encodes perhaps 5000 to 10000 the systematic pursuit of family studies to identify

genes. As with all human , only a very additional loci causing human genetic disease, as http://jmg.bmj.com/ small minority of the genes on chromosome 4 have well as facilitate the regional localisation of newly been identified. Taking together all genes, pseudo- cloned genes. genes, surface antigens, fragile sites, and anony- mous DNA segments given symbols, 69 loci Genes mapped to chromosome 4 had been officially assigned to the chromosome at the Human Gene Mapping Workshop 8.' These loci Thirty-one genes or have been mapped have been mapped by many different techniques to chromosome 4 by a variety of methods and they

including somatic cell genetics, dosage studies, and are listed in the table. Many of the genes were on September 26, 2021 by guest. Protected family studies, but recombinant DNA methods have assigned purely by traditional methods, such as produced the bulk of the assignments. The chromo- family studies, dosage in cells with chromosomal some is second only to the and aberrations, and somatic cell genetics. The loci in the number of cloned sequences encoding albumin (ALB), vitamin D binding available.2 At least 16 of the cloned segments (GC), and the (FGA, FGB, FGG) were represent known genes or pseudogenes (table), while originally mapped to chromosome 4 by linkage the remainder are anonymous DNA fragments with analysis or dosage experiments, but when each of no known function. The vast majority of DNA these genes was cloned it was possible to confirm the segments assigned to chromosome 4 detect res- assignments directly by recombinant DNA tech- triction fragment length polymorphisms (RFLPs). niques.3-15 Several of the genes on chromosome 4, With the great number of new markers now avail- such as (IL2) and epidermal growth able, it is expected that a genetic linkage map factor (EGF), were mapped only after cloning of encompassing the entire chromosome will soon be cDNAs permitted DNA hybridisation to panels of somatic cell hybrids or in situ hybridisation. Recei%ekl for puthlication 10 chruarn 1986. Two of t4e genes that have not yet been isolated, Accepted for- ptlication 12 Fchruiar% 1986. PGM2 and PEPS, encode the biochemical activities 193 J Med Genet: first published as 10.1136/jmg.23.3.193 on 1 June 1986. Downloaded from

194 Jan1les F Gusella, TConrad Gillianlw, MarcY E MacDonald, ShirleY V Cheng, and Rudolph E Tanzi

TABLIE Genes ,mapped to chromiosome 4*. Genc1 nDc,cripxiiop Loaeliio,, C'loned¢ (( 1 DN.-t

HD Htintingion' dl.ises. p16. linkCLd to D41IO 60 68 R 112 Processcd pstcudogenc of raf p15-ptcr + 32 oncog.lctt PGM2 Phosphoglticommtasc2 pl4-ql2 16 18 PI.PPS PcptidlaseS pll-q12 18 21 PP. T Phoslphorihos\Ilp! rophosphatc ptcr-.q21 22 amidotransferasc MT2P1 Mctallothioncin 2 processed pl I-q21 + 33 35 psetidlogenc Il P Alphafetoprotcin q I-q13 + 6 23 ILB Alhbiuimin qll-ql3 + 3 7 23 HP II'P Hereditarl persislence of Linkcd to lLB 53 alphafletoproltin G( GiGotip specificcotiiponent. %itamin ql2-ql3 + 3 8 10 D hinding protein I SSP8 Argininosticcinatc s\nthcta.sc q2l-qtec- + 36 psetidogenc 8 DGII Dcntinogcncsis iimperfecia Linkcd to GC 57 59 ADHI deh\drogenase. class q21-q25 + 25 alpha chain IDH2 Alcohol deh%drogenase. clatss q21-q25 + 24 25 beta chain ,1DH3 Alcohol dch\diogenase. class q2l-q25 + 24 gaiimma chain .IDHS Alcohol deh\drogenase. class Ill q21_-q25 26 chi chain I DH F-ormttaldehWde deh\drogenase q2l-q25 73 76 IG Aspartflglttcosamttinidasc q21-qtcr 54 55 IEGIFFpidcrinal giowth factor q25--q27 + 40 42 IL2 T cell growth factor. interlettkin 2 q26-q28 + 38 39

PG. Fibhinogn alpha chain q26-q28 + 13 15 copyright. FGB beta chain q26-q28 + 13 15 IGG 1-ibrinogen gaititita chain q26-q28 + 11 13 15 MNS MNS hlood grotip. gl\cophorins A & B q28-q3l 27 3045 Sl Stolt/fttl hlood grotip Linked to MNS 46 47 TYS Sclerot%losis Linked to MNS 56 (D2 LettcoC\tC SLurface antigen 5 ICD2p5O Not regionally imiapped 77 MDI I T cell antigen detected hy Not regionally mapped 78 ittonoclonal Ah MI('16 ALL antigen detected hy Not regionall\ titapped 79 ittonoclonal Ah http://jmg.bmj.com/ QDPR Qttinoid dih\ dropterlidine redItIctase Not regionally titapped + 49 51 NA c- proto-oncogene Not regionally niapped + 37 NA=not assigned. The list does not incltide anonytmotts DNA seqtiences or fragile sites which can he fotind in refeiences I and 2. most frequently used as markers for the presence data suggesting that it is a member of the same gene of chromosome 4 in somatic cell hybrid experi- family."0 Further down the long arm, there is a set of on September 26, 2021 by guest. Protected ments.86-2' The PPAT locus, also not yet cloned, genes encoding alcohol dehydrogenases.24-26 It is was mapped by complementation in auxotrophic likely that when these are fully sequenced and mutant hamster cells deficient in the phos- characterised they will consist of related sequences phoribosylpyrophosphate amidotransferase.22 This tightly clustered on the chromosome. The MNS makes PPA T a potential selectable marker for blood group locus results from polymorphisms in directed somatic cell genetic studies of chromosome (MN) and glycophorin B (Ss), two 4. related encoded by tightly linked DNA The approximate locations of the known genes sequences.27-30 A third glycoprotein from red blood that have been regionally mapped on chromosome 4 cell membranes, , might well be are shown in the figure. Several of the genes appear encoded in the same region.3' Finally, towards the to cluster into families of related sequences. Below bottom of the long arm there is a cluster of three the , ALB and AFP encode related fibrinogen genes which are contiguous in a 50 proteins and are separated by only a few thousand kilobase segment.' 5 base pairs.23 Moreover, the cloning of GC which is In contrast to the clustering of the functional gene tightly linked to the ALB locus has yielded sequence families, there are three loci on chromosome 4 that J Med Genet: first published as 10.1136/jmg.23.3.193 on 1 June 1986. Downloaded from

Molecular genetics ofhumpan chromiiosonoe 4 195

HD Conventional genetic markers, GC and MNS 16 D4SIO Two of the loci mapped to chromosome 4 by 5.3 conventional methods, GC and MNS, show consider- parm 15.115.2 able polymorphism, placing them among the more informative expressed genetic markers. GC, group 14 specific component or vitamin D binding protein, 13 displays polymorphism that is detectable as differ- 12 PGM2 ences in electrophoretic mobility of the It PEPS protein. 12 ALB has a polymorphism information content (pic) of AFP 0O33.~o.344 13.1 GC 13.2 DGI1 The MNS blood group marker actually results 13.3 from two tightly linked genes.27-30 The first, en- 21.1 21.2 coding glycophorin A, the major red cell surface 21.3 FDH ADHI protein, displays a sequence polymorphism at its 5' 22 ADH2 end that determines the M or N specificities. This ADH3 23 ADH5 protein is highly glycosylated, with the presence of 24 the appropriate sugar residues being essential for 25 detecting the appropriate specificities.30 Glyco- EGF q arm 26 phorin B, a less abundant red cell surface protein, has IL2 an identical 5' amino acid sequence to the N form of 27 FGA glycophorin A. The remaining sequence diverges, FGB 28 FGG however, and a polymorphism in this region results in either S or s , again detected as antigenic 31.1 MNS differences. Since the sequences encoding the two 312 SF

polymorphisms are close together in the , the copyright. 31.3 TYS resultant haplotypes are used, in practice, as alleles 32 for a single locus. Less frequent variants at these two loci have produced proteins that lack either M or N 33 activity. or that appear to be fusions between 34 glycophorins A and B.45 The MNS marker has a pic 35 of 0 64, making it second only to HLA in informa-

tiveness among the expressed markers.44 http://jmg.bmj.com/ FHGURI. Regionallv locaulised( genes on chromiosomne 4. The A third expressed polymorphism mapping to ordler ain(d regional localisations are on/i approxilmiate. chromosome 4 is the Stoltzfus blood group mar- ker.46 4 Like MNS, Stoltzfus (SF) is detected as each represent a processed , whose func- differences in the antigenic determinants on red cell tional counterpart is located on an entirely different membranes. It is genetically linked to the MNS chromosome. RAF2, MT2PI, and ASSP8 are pro- marker and is not frequently used in genetic linkage cessed pseudogenes homologous to the RAFI proto- studies. on September 26, 2021 by guest. Protected oncogene (RAFl) on , the metal- Regional localisation of the GC and MNS markers lothionein-2 gene (MT2) on , and the by dosage studies in families with rearranged argininosuccinate synthetase gene (ASS) on chromo- chromosomes places them towards opposite ends of some 9, respectively.32- 36 the long arm. Despite this apparently great physical The recent mapping of the human homologue of separation, very extensive family studies have demons- v-kit, the viral oncogene from the Hardy-Zuckerman trated statistically significant but distant linkage 4 feline sarcoma virus (HZ4-FeSV), to chromosome 4 between the two loci. This linkage is detectable in is the first indication of a potential oncogene on male meioses, presumably reflecting a greater fre- this autosome.3' The only previous implication of quency of recombination on the long arm of chromosome 4 in carcinogenesis has been the chromosome 4 in females than in males.28 48 observation of a translocation of the long arms of chromosomes 4 and 11 in some cases of acute Disease genes mapped to chromosome 4 lymphocytic leukaemia. This translocation joins the ETSI oncogene locus from and a In general, genetic can be mapped to chromosome 4 sequence that has not yet been chromosomes either by family studies to detect identified.43 coinheritance with a polymorphic marker or by J Med Genet: first published as 10.1136/jmg.23.3.193 on 1 June 1986. Downloaded from

196 James F Gusella, T Conrad Gillian,i, Marc!' E MacDonald, Shirley V Cheng, and Rudolph E Tanzi demonstrating an alteration in a gene product from a informative locus displaying greater than 90% known locus. The latter is more common, since heterozygosity.64 The DNA marker is linked to HD infrequent variants have been described for many at a distance of 4 to 5% recombination (1-lod well characterised proteins. For chromosome 4, both confidence interval 1-8%).1 approaches have contributed only a few genetic The two loci have recently been mapped to the defects to the map. terminal band of the short arm, 4p16.6568 Gusella The QDPR locus encoding dihydropteridine et al65 showed that in patients with Wolf-Hirschhorn reductase is the presumed site of the defect in type II syndrome, a congenital defect caused by the hetero- phenylketonuria where patients do not respond to a zygous of this region, the D4S10 locus is also phenylalanine free diet.49"5 This enzyme is in- deleted. This result has been confirmed by in situ volved in the production of biopterin, a necessary hybridisation by several groups.66-68 In one study it cofactor for the enzyme phenylalanine hydroxylase, was possible using patients with interstitial deletions which is defective in type I phenylketonuria. Anal- of the short arm to narrow the assignment of D4S10 buminaemia is a rare condition in which subjects fail to the terminal half of 4pl6.1, one of three sub-bands to produce albumin from the ALB locus on the long seen in prometaphase banding experiments.68 The arm of chromosome 4.52 A second condition, location of D4S10, and by inference HD, to the hereditary persistence of alphafetoprotein (HPAFP), terminal part of the short arm explains the failure to is closely linked to the AFP and ALB loci and may detect the disease locus by linkage to either GC or represent a in regulatory sequences at the MNS on the long arm.60 alphafetoprotein locus. Recently, the AGA locus The mapping of HD to chromosome 4 has encoding , the enzyme defi- provided the impetus to generate large numbers of cient in the lysosomal storage disorder aspartyl- anonymous DNA markers for this autosome. These glucosaminuria, has been assigned to the long arm of' now represent more than half of all the assigned loci chromosome 4.54 55 on chromosome 4. A few markers have been mapped Genetic linkage studies have been modestly success- using somatic cell hybrid panels after they were ful on chromosome 4, although the high quality of identified in searches for RFLPs using DNA probes copyright. GC and MNS as markers makes it somewhat chosen at random from genomic DNA.60 69-71 The surprising that this approach has not identified more majority of the anonymous DNA sequences, how- disease loci. In fact, only two disease genes have been ever, have come from libraries enriched for chromo- located using these markers. In 1968, sclerotylosis some 4 sequences by flow sorting of metaphase (TYS), an autosomal dominant skin disorder, was chromosomes.7' 72 Subsequent screening for RFLPs provisionally linked to MNS, although this assign- has revealed that most of these can be successfully ment has never been confirmed.56 In 1982, Ball et al used as genetic markers in linkage studies. A total of http://jmg.bmj.com/ showed linkage of dentinogenesis imperfecta (DGII), 37 anonymous DNA loci had been described for a defect in dentition, to GC.57 58 This linkage has chromosome 4 by Human Gene Mapping Workshop been confirmed by Conneally et al.59 8, and 30 of these represent useful polymorphic markers.'2 Many additional anonymous DNA loci are currently being characterised (Gusella et al, DNA markers on chromosome 4 unpublished results).

The advent of recombinant DNA techniques for Of the cloned genes and pseudogenes from on September 26, 2021 by guest. Protected directly detecting polymorphisms in DNA has pro- chromosome 4, 12 detect RFLPs useful in linkage duced the potential for detecting loci by linkage analysis, although this number is slightly misleading anywhere in the genome. The discovery of a DNA due to the tight clustering of some related genes' marker linked to the Huntington's disease (HD) locus (Gusella et al, unpublished results). Overall, including on chromosome 4 was the first successful use of this both anonymous sequences and cloned genes, there approach for an autosomal disease.60 HD is a late are currently more DNA markers for chromosome 4 onset neurodegenerative disorder that shows auto- than for any other autosome.3 somal dominant transmission. The initial linkage has No additional markers linked to HD have yet been now been confirmed in several families, although the identified from this pool of DNA loci, perhaps possibility of non-allelic heterogeneity in HD has not because of its terminal location on the short arm. An yet been excluded.6' - 63 The linked marker, D4SIO, is intensive effort is now under way to saturate 4pl6 detected using the anonymous single copy DNA with new DNA markers. These are needed to probe G8. Although originally two polymorphic increase the accuracy and applicability of any HindlII sites were used to generate four haplotypes presymptomatic or prenatal diagnostic test pro- for this locus, the discovery of several additional cedures in HD which could potentially be based on RFLPs with other has made this a highly linkage analysis. They will also be required to refine J Med Genet: first published as 10.1136/jmg.23.3.193 on 1 June 1986. Downloaded from

Molecular genetics of human chromosome 4 197 genetic mapping of the HD locus in anticipation of Bowmain BH. Maipping of hiiuman group-specific comiiponent to cloning and characterising the defect. chromiosomic 4 ( itoqenct (Cel Genct 1985:40:710. A detailed linkage map of 4p16 will not be the only Olaisen B. Teisberg P. Gedde-Dahl T. Mesag B. Fibrinogen gamnma chain loCLIs is on chiomilosomiic 4 in ima.ln. ()rtogenet Cell byproduct of the search for the HD gene. This effort Genet 1984:37:560. has already produced a large number of anonymous 12 Olaisen B. Teisberg P. Gedde-Dihl T. Fibrinogen gaimiil.zi-chalin DNA markers from both the long and short arms. locuIs is on chromiiosoiiic 4 in imain. Htv)ii Genet 1982:61:24 6. These RFLPS, along with those detected cloned 3Henry 1. LJz in G. Weil D. et cil. The genes coding for A alpha-. B by beta-. alnd gaiimmia- chaiins of fibrinogen map to 4q2. Ain J Hiiiii genes from chromosome 4, are currently being traced Genet 1984 36:760 8 through large reference pedigrees by several groups. 4 Humphries S. Imam A. Robbins T. it il. Thc identification of a This combined effort will soon generate a complete DNA polymorphism of the alpha fibrinogen gene. aind the all of chromosome 4. The vast regional assignimient of the human fibr-inogen genes to 4q26-qter. linkage map spanning Humiii Genti 1984:68:148 53. of as on array yet unidentified genes chromosome 4 5 Kant JA. Fornaice AJ. Saxe D. Sinion Ml. McBride OW. undoubtedly include several involved in genetic Crabtree GR. EvoluLtion and organization of the fibrinogen disease. The availability of a selection of spaced locus on chromosonme 4: gene duiplication accompanied by markers for this autosome will transposition aind inversion. Proc Ntil Acail Sci LtSA 1985:82: polymorphic permit 2344-8. directed family studies with more efficient and " Wijnen LMM. Grzeschik KH. Pearson PL. Meera Khan P. The powerful data analysis leading to the eventual huIman PGM-2 and its chromosomiial location in man-mouse localisation of these defects. hybrids. Huiii Genct 1977:37:217 78. 1 Sparkes RS. Mohandas T. Sparkes MC. ShLIlkin JD. Regional localization of human phosphoglucomilutase-2 locus on chromo- Preparation of this manuscript was supported by sonie 4. Exp Cell Rc.s 1978:111:492-5. NIH grants NS16367 and NS20012. JFG is sup- 1 Bocian M. Mohandas T. Sparkes RS. Funderburk S. Peptidase ported by the Searle Scholar Program/Chicago S (PEPS) and phosphoglucomILtase 2 (PGM) loci on the short arm of human chromosomiie 4. Cell Genet 1979:25:138. Community Trust. TCG and MEM are recipients Critogenct '9 Shows TB. Brown JA. Eddy RL. it al. Assignment of peptidase S of the Anna Mitchell Fellowship and the Grace E (PEPS) to chromosome 4 in man using somatic cell hybrids. Neuman Fellowship, respectively, from the Heredi- Humo GenetC 1978:43:119 25. tary Disease Foundation. SVC received a fellowship 2( Brown S. Lalley PA. Minna JD. Assignment of the gene for copyright. from the National Disease Association. peptidase S (PEPSI to chromosoine 4 in man and confirmation Huntington's of peptidase D (PEPD) assignment to . CYtogenet Cell Genet 1978:22:167 -71. References 21 Schmutz SM. Simpson NE. Suggested assignment of peptidase S (PEPS) to 4pll 4ql2 by exclusion Llsing gene dosage. account- Kidd KK. Gusella JF. Report of the committee on the genetic ing for variability in fibroblasts. Huu,mi G(n(t 1984:64:134-8. constitution of chromosomes 3 and 4. HGM8. CItoqcnet Cell 22 Stanley W. Chu EHY. Assignment of the gene for phosphoribo-

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198 James F Gusella, T Conrad Gillianm, MarcY E MacDonald, ShirleY V Cheng, and Rudolph E Tanzi

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4' Botstein D. White RL. Skolnick M. Davis RW. Constriuction of Wang HS. Greenberg CR. Kalousek D. GusellaJ. Horsman D. http://jmg.bmj.com/ a genetic linkage map in man using restriction fragment length Hayden MR. Subregional assignment of the linked marker for Htintington disease by in situ hybridization. 45 polymorphisms. Am J Hiiium Genet 1980:32:314 31. (D4SlO) Mawby WJ. AnsteeDJ. Tanner MJ. lmmtinochemical evidenceh8CGtogenet Cell Genet 1985:40:772. for hybrid sialoglycoproteins of human erythrocytes. Natuire Magenis E. GusellaJ. Weliky K. Haight G. Sheehy B. Huntington disease-linked (HD) restriction fragment length 4h 1981:291:161 2. Bias WB. Meyers DA. Segregation and linkage analysis of the polymorphism localized to band p16 of chromsome 4 by in situ Stoltzfus blood grouip.(C'togenet(ell Genet 1979;25:137. h9 hybridization. Crvtogenet Cell Genet 1985:40:685. 4' Bias WB. Meyers DA. Fuirther data on the linkage between the Kao FT. Hartz JA. Law ML. Assignment of a random human MNS and Stoltzfus blood group systems. Cell Genet DNA segment D4ER11 to the long arm of human chromosome

CYtogenet on September 26, 2021 by guest. Protected 4. Cell Genet 1984:37:506. 48 1982:32:254. C.vtogenet Falk C. Huss i. Estimates of recombination frequencies betweenG0Gusella iF. Recombinant DNA techniques in the diagnosis of the chromosome 4 markers MNS. GC. and PLG.( Cell inherited disorders. J Clin Ini-est (in press). 'C1togenet G illiam TC. Scambler P. Robbins . Ingle C. WilliamsonR. 4 Genet 1985:40:626. Kaufman S. Holtzman NA. Milstein S. Butler II. Krumholz A. Davies KE. The position of threc restriction fragment length Phenylketonuiria due to a deficiency of dihydropteridine reduc- polymorphisms on chromosome 4 relative to known genetic markers. Genet 1984:68:154--8. 5" tase. N Engl J Med 1975:293:785 90. Hi,iii Kuhl P. Olek K. Wardenbach P. Grzeschik KH. Assignment of 72 Gilliam TC. Healey S. Tanzi R. Stewart G. Gusella i. a gene for human quinoid-dihydropteridine reduictase (QDPR) Polymorphic DNA probes from a human chromosome 4 library. to chromosomeHum,114. Genet1979;53:4799. ?3 Crtogenet Cell Genet 1985:40:641. " Lockyer iM. Kidd Vi.Ledley FD. Milstein S. Kaufman S. Woo Meera Khan P. Wijnen LMM. Hagemeijer A. Pearson PL. SLC. of human dihydropteridine reductase. Human formaldelhyde dehydrogenase (FDH) and its assignment Amii J Huitii Genet 1985:37:165A. 7 to chromosome 4. Crtogenet Cell Genet 1984:38:112-5. 52 Murray iC. Demnopolous CM. Lawn RM. Motulsky AG. Van Cong N. Gross MS. Jegou-Foubert C. Frezal J. Form- Molecular genetics of : restriction enzyme aldehyde dehydrogenase and chromosome 4. Crtogenet Cell fragment length polynmorphisms and analbLuminemia. Proc Natl Genet 1985:40:765 6. 5 S. Carlock L. Wasmuth Smith M. Regional 5' Acad Sc-i USA4 1983:80:5951 5. Hiroshige J. Ferguson-Smith MA. Yates iRW. Kelly D. et al. Hereditary assignment of human formaldehyde dehydrogenase (FDH) persistence of alphafetoprotein maps to the long arm of 4q21 4q25.Co('togenet Cell Genet 1985:40:651 2. chromosome 4. CrtoCenet C9llGenet 1985:40:628. 7t" Van der Goes R. Geurts van Kessel A. Hagemeijer A. Wijnen J Med Genet: first published as 10.1136/jmg.23.3.193 on 1 June 1986. Downloaded from

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LMM, Meera Khan P. Localization of human FDH to 79 Katz F, Povey S, Parkar M. et al. Chromosome assignment of 4q21-qter. Cytogenet Cell Genet 1985;40:766. monoclonal-antibody defined determinants on leukemic cells. 77 Geurts van Kessel AHM, Stoker K, Claas FHJ, van Agthoven Eur J Inimnunol 1983;13:1008-13. AJ, Hagemeijer A. Assignment of the leukocyte group 5 surface antigens to human chromosome 4. Tissue Antigens 1983;21: 213-9. Correspondence and requests for reprints to Dr J F '78 Peters PM, Kamarck ME, Hemler ME. Strominger JL, Ruddle Gusella, Neurogenetics Laboratory, Massachusetts FH. Genetic and biochemical characterization of human General Hospital, Boston, Massachusetts 02114, lymphocyte cell surface antigens. J Exp Med 1984;159-1441-54. USA. copyright. http://jmg.bmj.com/ on September 26, 2021 by guest. Protected

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