J Med Genet: first published as 10.1136/jmg.25.11.721 on 1 November 1988. Downloaded from Gene mapping and medical genetics Journal of Medical Genetics 1988, 25, 721-731 Human chromosome 8 STEPHEN WOOD From the Department of Medical Genetics, University of British Columbia, 6174 University Boulevard, Vancouver, British Columbia, Canada V6T IWS. SUMMARY The role of human chromosome 8 in genetic disease together with the current status of the genetic linkage map for this chromosome is reviewed. Both hereditary genetic disease attributed to mutant alleles at gene loci on chromosome 8 and neoplastic disease owing to somatic mutation, particularly chromosomal translocations, are discussed. Human chromosome 8 is perhaps best known for its In an era when complete sequencing of the human involvement in Burkitt's lymphoma and as the genome is being proposed, it is appropriate for location of the tissue plasminogen activator gene, medical geneticists to accept the challenge of defining by copyright. PLAT, which has been genetically engineered to the set of loci that have mutant alleles causing provide a natural fibrinolytic product for emergency hereditary disease. The fundamental genetic tool of use in cardiac disease. Since chromosome 8 repre- linkage mapping can now be applied, owing largely sents about 5% of the human genome, we may to progress in defining RFLP markers.3 4 This expect it to carry about 5% of human gene loci. This review will focus on genetic disease associated with would correspond to about 90 of the fully validated chromosome 8 loci and the status ofthe chromosome 8 phenotypes in the MIM7 catalogue.' The 27 genes linkage map. assigned to chromosome 8 at the Ninth Human Gene Mapping Workshop (Paris, September 1987) Disease loci thus represent a third of the expected number. In http://jmg.bmj.com/ addition, six loci corresponding to fragile sites, three Inherited diseases that are thought to result from pseudogenes, and four gene-like sequences were mutant alleles at defined gene loci on chromosome 8 reported.2 Nevertheless, this is but a small fraction are shown in table 1. Loci that have been regionally of the 500 to 5000 gene loci expected from a genome localised are shown in the figure. The EBSI, SPHI, that contains between 10 000 and 100 000 genes. and VMD1 loci are defined by the disease associated alleles, while the LGCR locus, which is deleted Received for publication 22 June 1988. in Langer-Giedion syndrome, is cytogenetically Accepted for publication 11 July 1988. defined. on September 28, 2021 by guest. Protected TABLE 1 Chromosome 8 loci that may have disease-causing alleles. Disease Locus symbol McKusick No Localisation Cloned DNA RFLP Dominant disorders Epidermolysis bullosa EBSI 13195 8q Hereditary thrombotic disease PLAT 17337 8pI2-qII 2 + + Langer-Giedion syndrome LGCR 15023 8q24 1-q24 12 Hereditary spherocytosis SPH1 18290 8p2l-l-pl-22 Congenital goitre TG 18845 8q24-2-q24-3 + + Vitelliform macular dystrophy VMDI 15370 8q Recessive disorders Osteopetrosis with renal tubular acidosis CA2 25973 8q22 + + Congenital adrenal hyperplasia 11B CYPIIB 20201 8q21 + Haemolytic anaemia GSR 23180 8p2l Hyperlipoproteinaemia LIPD 23860 8p22 + + 721 J Med Genet: first published as 10.1136/jmg.25.11.721 on 1 November 1988. Downloaded from 722 Stephen Wood 2i considered to be a distinct variant from the EBS 23.1 D8S7 Koebner orEBS Weber-Cockayne type, was reported in a single, large Norwegian family.5 The mutation 22 LIPD was thought to originate in the community of Ogna 21.3 in south-western Norway.5 Among 246 family 21.2 IGSR 21.1 members, 93 cases were identified and close linkage 12 SPHI to GPT established6 (0=0-05, Z=10-98). The recent placement of GPT and the chromosome 8 locus 11.2 TG 7 on the same linkage group enables the EBSI it:t locus to be assigned to chromosome 8. The possibility 11:11 1A that these three dominant forms of EBS are allelic can now be evaluated by linkage analysis with DNA 12 markers. 13 PLASMINOGEN ACTIVATOR DEFICIENCY AND THE 21.1 PLAT GENE Three families have been reported where defective 21.2 CYPIlB release of vascular plasminogen activator, inherited 21.3 as a dominant trait, was associated with a history of deep venous thromboses.8-0 The deficient fibrino- 22.1 22.2 lytic activity in these families may reflect a primary 22.3 defect of the PLAT structural gene. The Bowes melanoma cell line which produces 23 plasminogen activator has been used for isolation of cDNA clones.'1 12 Subsequently, phage'3 andby copyright. cosmid13 14 clones have been isolated and expressed 24.1 |LGCR in L cells.'5 The entire gene, which exceeds 32 kb 24.2 encompassing 14 exons, has been sequenced.'6 The 24.3 gene has been assigned to chromosome 8 using cell 8 hybrids'7-'9 and sublocalised to the pericentromeric20 region 8p12-q11 221 by in situ hybridisation. A common RFLP has been reported.'7 FIGURE Regional localisation ofdisease loci and linkage map for human chromosome 8. Both the physical and LANGER-GIEDION SYNDROME CHROMOSOME http://jmg.bmj.com/ linkage relationships are shown for the loci D8S7, PLA T, REGION (LGCR) D8S5, CA2, and TG. The remaining linked loci are defined The Langer-Giedion syndrome (LGS) has features by proprietary6probes ofCollaborative Research which include characteristic facies, sparse hair, and Incorporated' '(for clarity the CRIprefix is not indicated in cone shaped epiphyses that resemble trichorhino- thisfigure). The numbers indicate sex average phalangeal syndrome type I (TRP I). LGS, which is recombination between adjacent loci. A broken line is used sometimes called TRP II, includes additional to indicate unknown linkage distance. features of mental retardation, microcephaly, and multiple exostoses that are generally not seen in on September 28, 2021 by guest. Protected The remaining loci are defined by their bio- TRP I. Recently 36 cases of LGS were reviewed.22 chemical gene product which is abnormal or absent Since the initial report23 of an 8q terminal in the associated disease. Most of these structural deletion in LGS, various deletions2435 as well as gene loci have been cloned and RFLP markers complex rearrangements36 37 have been described in defined, so that it is possible to show cosegregation affected patients. Cytogenetic review38 suggested of the disease with the structural gene locus. For that apparent non-deletion casesr9 might exhibit most disorders this preliminary step towards subtle features of asymmetry between chromosome defining the nature of the mutant allele(s) has not homologues. The minimum critical region ofdeletion yet been accomplished. that is involved in LGS has been the subject of many reports.29 36 38 Recently, deletion of 8q24 11- EPIDERMOLYSIS BULLOSA SIMPLEX, OGNA TYPE q24-12 has been suggested as the critical region for (EBS1) LGS33 consistent with a reported patient in whom Dominantly inherited EBS, characterised by a the TG locus (at 8q24.2-q24.3) was not involved.40 generalised bruising tendency of the skin and hence It has been suggested that the only consistent J Med Genet: first published as 10.1136/jmg.25.11.721 on 1 November 1988. Downloaded from Human chromosome 8 723 clinical feature that distinguishes LGS from TRP I is to 8pll for the SPH1 gene.55 A family has been the presence of cartilaginous exostoses in the former reported where hereditary spherocytosis and gluta- condition. 38 Furthermore, interstitial deletions of thione reductase deficiency segregated independ- chromosome 8,4 43 including two cases with dele- ently56 suggesting that these genes are not closely tion of 8q24.12,42 43 have been reported in patients linked, although the type of hereditary spherocytosis with TRP I. This suggests that the larger LGS was not determined. deletion may uncover an exostosis gene. Dominantly More recently, two dysmorphic sibs affected with inherited multiple exostoses may involve this same congenital spherocytosis were found to share a locus, although no cytogenetically apparent deletion deletion of chromosome 8, del(8)(pll-1p21-1). The of chromosome 8 has been found. parents were both haematologically and chromo- Most cases of LGS are sporadic, resulting from somally normal.57 This interesting case presumably de novo deletions or presumed deletions. One case represents an example of chromosomal germ line report concerned a patient whose father had an mosaicism.57 An additional case of interstitial inversion, inv(8)(q22-3q24.13).5 Although this may deletion of chromosome 8, del(8)(p11-22p21-1), be a chance observation, the suggestion that inver- associated with spherocytosis has been reported. sions may predispose to unequal recombination45 is Spherocytosis in these deletion patients is probably of general interest and concern46 to medical gen- the result of uniplex (that is, single copy) gene eticists. A familial syndrome with features of LGS expression. This indicates that hereditary sphero- cosegregating with an 8q inversion has been cytosis owing to the SPH1 locus is likely to be an reported.47 An affected father and daughter have amorph or null allele and not the type I hereditary been reported although cytogenetic findings were spherocytosis associated with a neomorph of , not available.48 Finally, a patient reported with spectrin. normal intelligence and a minimal deletion33 could Recently, cDNA clones for P spectrin have been be expected to transmit LGS as a dominant trait. isolated.59 This has allowed localisation of this gene to chromosome 14 by hybridisation to dot blots of by copyright. HEREDITARY SPHEROCYTOSIS (SPH1) flow sorted chromosomes.59 Linkage between her- Hereditary spherocytosis is a common, usually editary spherocytosis and Gm has been reported54 dominantly inherited, haemolytic anaemia caused with a lod score of 3-42 at 0=0-22. While the odds by defects in the red cell cytoskeleton.49 The of heterogeneity to homogeneity of 1:2-04 neither prevalence has been estimated to be about 1 in 5000 favoured nor excluded heterogeneity, the largest Caucasians.50 Both biochemical and genetic studies four families of the 11 families studied made the indicate that hereditary spherocytosis is hetero- major contribution to the lod score.