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. 1999 Jan;64(1):165–171. doi: 10.1086/302187

Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping.

M Ohadi 1, M R Lalloz 1, P Sham 1, J Zhao 1, A M Dearlove 1, C Shiach 1, S Kinsey 1, M Rhodes 1, D M Layton 1
PMCID: PMC1377714  PMID: 9915955

Abstract

Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.

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Selected References

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  1. Abella E. M., Artrip J., Schultz K., Ravindranath Y. Treatment of familial erythrophagocytic lymphohistiocytosis with cyclosporine A. J Pediatr. 1997 Mar;130(3):467–470. doi: 10.1016/s0022-3476(97)70212-9. [DOI] [PubMed] [Google Scholar]
  2. Aricò M., Nespoli L., Maccario R., Montagna D., Bonetti F., Caselli D., Burgio G. R. Natural cytotoxicity impairment in familial haemophagocytic lymphohistiocytosis. Arch Dis Child. 1988 Mar;63(3):292–296. doi: 10.1136/adc.63.3.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barbosa M. D., Nguyen Q. A., Tchernev V. T., Ashley J. A., Detter J. C., Blaydes S. M., Brandt S. J., Chotai D., Hodgman C., Solari R. C. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature. 1996 Jul 18;382(6588):262–265. doi: 10.1038/382262a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blanche S., Caniglia M., Girault D., Landman J., Griscelli C., Fischer A. Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single-center study of 22 cases. Blood. 1991 Jul 1;78(1):51–54. [PubMed] [Google Scholar]
  5. Brownstein M. J., Carpten J. D., Smith J. R. Modulation of non-templated nucleotide addition by Taq DNA polymerase: primer modifications that facilitate genotyping. Biotechniques. 1996 Jun;20(6):1004-6, 1008-10. doi: 10.2144/96206st01. [DOI] [PubMed] [Google Scholar]
  6. Del Sal G., Ruaro M. E., Philipson L., Schneider C. The growth arrest-specific gene, gas1, is involved in growth suppression. Cell. 1992 Aug 21;70(4):595–607. doi: 10.1016/0092-8674(92)90429-g. [DOI] [PubMed] [Google Scholar]
  7. Demetrick D. J., Zhang H., Beach D. H. Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. Cytogenet Cell Genet. 1996;73(3):250–254. doi: 10.1159/000134349. [DOI] [PubMed] [Google Scholar]
  8. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  9. Egeler R. M., Shapiro R., Loechelt B., Filipovich A. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 1996 Nov;18(4):340–345. doi: 10.1097/00043426-199611000-00002. [DOI] [PubMed] [Google Scholar]
  10. Evdokiou A., Webb G. C., Peters G. B., Dobrovic A., O'Keefe D. S., Forbes I. J., Cowled P. A. Localization of the human growth arrest-specific gene (GAS1) to chromosome bands 9q21.3-q22, a region frequently deleted in myeloid malignancies. Genomics. 1993 Dec;18(3):731–733. doi: 10.1016/s0888-7543(05)80388-x. [DOI] [PubMed] [Google Scholar]
  11. FARQUHAR J. W., CLAIREAUX A. E. Familial haemophagocytic reticulosis. Arch Dis Child. 1952 Dec;27(136):519–525. doi: 10.1136/adc.27.136.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Falini B., Pileri S., De Solas I., Martelli M. F., Mason D. Y., Delsol G., Gatter K. C., Fagioli M. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood. 1990 Jan 15;75(2):434–444. [PubMed] [Google Scholar]
  13. Favara B. E., Feller A. C., Pauli M., Jaffe E. S., Weiss L. M., Arico M., Bucsky P., Egeler R. M., Elinder G., Gadner H. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997 Sep;29(3):157–166. doi: 10.1002/(sici)1096-911x(199709)29:3<157::aid-mpo1>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  14. Fischer A., Cavazzana-Calvo M., De Saint Basile G., DeVillartay J. P., Di Santo J. P., Hivroz C., Rieux-Laucat F., Le Deist F. Naturally occurring primary deficiencies of the immune system. Annu Rev Immunol. 1997;15:93–124. doi: 10.1146/annurev.immunol.15.1.93. [DOI] [PubMed] [Google Scholar]
  15. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  16. Hasle H., Brandt C., Kerndrup G., Kjeldsen E., Sørensen A. G. Haemophagocytic lymphohistiocytosis associated with constitutional inversion of chromosome 9. Br J Haematol. 1996 Jun;93(4):808–809. doi: 10.1046/j.1365-2141.1996.d01-1718.x. [DOI] [PubMed] [Google Scholar]
  17. Henter J. I., Elinder G., Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991 Feb;18(1):29–33. [PubMed] [Google Scholar]
  18. Henter J. I., Elinder G., Söder O., Hansson M., Andersson B., Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991 Dec 1;78(11):2918–2922. [PubMed] [Google Scholar]
  19. Henter J. I., Elinder G., Söder O., Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991 Apr;80(4):428–435. doi: 10.1111/j.1651-2227.1991.tb11878.x. [DOI] [PubMed] [Google Scholar]
  20. Hirst W. J., Layton D. M., Singh S., Mieli-Vergani G., Chessells J. M., Strobel S., Pritchard J. Haemophagocytic lymphohistiocytosis: experience at two U.K. centres. Br J Haematol. 1994 Dec;88(4):731–739. doi: 10.1111/j.1365-2141.1994.tb05111.x. [DOI] [PubMed] [Google Scholar]
  21. Janka G. E. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983 Jun-Jul;140(3):221–230. doi: 10.1007/BF00443367. [DOI] [PubMed] [Google Scholar]
  22. Komp D. M., McNamara J., Buckley P. Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes. Blood. 1989 Jun;73(8):2128–2132. [PubMed] [Google Scholar]
  23. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  24. Ladisch S., Ho W., Matheson D., Pilkington R., Hartman G. Immunologic and clinical effects of repeated blood exchange in familial erythrophagocytic lymphohistiocytosis. Blood. 1982 Oct;60(4):814–821. [PubMed] [Google Scholar]
  25. Lander E. S., Botstein D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science. 1987 Jun 19;236(4808):1567–1570. doi: 10.1126/science.2884728. [DOI] [PubMed] [Google Scholar]
  26. Landman-Parker J., Le Deist F., Blaise A., Brison O., Fischer A. Partial engraftment of donor bone marrow cells associated with long-term remission of haemophagocytic lymphohistiocytosis. Br J Haematol. 1993 Sep;85(1):37–41. doi: 10.1111/j.1365-2141.1993.tb08642.x. [DOI] [PubMed] [Google Scholar]
  27. Le Deist F., Emile J. F., Rieux-Laucat F., Benkerrou M., Roberts I., Brousse N., Fischer A. Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet. 1996 Sep 14;348(9029):719–723. doi: 10.1016/S0140-6736(96)02293-3. [DOI] [PubMed] [Google Scholar]
  28. Mitelman F., Mertens F., Johansson B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet. 1997 Apr;15(Spec No):417–474. doi: 10.1038/ng0497supp-417. [DOI] [PubMed] [Google Scholar]
  29. Moynihan L. M., Bundey S. E., Heath D., Jones E. L., McHale D. P., Mueller R. F., Markham A. F., Lench N. J. Autozygosity mapping, to chromosome 11q25, of a rare autosomal recessive syndrome causing histiocytosis, joint contractures, and sensorineural deafness. Am J Hum Genet. 1998 May;62(5):1123–1128. doi: 10.1086/301824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nagle D. L., Karim M. A., Woolf E. A., Holmgren L., Bork P., Misumi D. J., McGrail S. H., Dussault B. J., Jr, Perou C. M., Boissy R. E. Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet. 1996 Nov;14(3):307–311. doi: 10.1038/ng1196-307. [DOI] [PubMed] [Google Scholar]
  31. Osugi Y., Hara J., Tagawa S., Takai K., Hosoi G., Matsuda Y., Ohta H., Fujisaki H., Kobayashi M., Sakata N. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997 Jun 1;89(11):4100–4103. [PubMed] [Google Scholar]
  32. Pastural E., Barrat F. J., Dufourcq-Lagelouse R., Certain S., Sanal O., Jabado N., Seger R., Griscelli C., Fischer A., de Saint Basile G. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nat Genet. 1997 Jul;16(3):289–292. doi: 10.1038/ng0797-289. [DOI] [PubMed] [Google Scholar]
  33. Perez N., Virelizier J. L., Arenzana-Seisdedos F., Fischer A., Griscelli C. Impaired natural killer activity in lymphohistiocytosis syndrome. J Pediatr. 1984 Apr;104(4):569–573. doi: 10.1016/s0022-3476(84)80549-1. [DOI] [PubMed] [Google Scholar]
  34. Reed P. W., Davies J. L., Copeman J. B., Bennett S. T., Palmer S. M., Pritchard L. E., Gough S. C., Kawaguchi Y., Cordell H. J., Balfour K. M. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nat Genet. 1994 Jul;7(3):390–395. doi: 10.1038/ng0794-390. [DOI] [PubMed] [Google Scholar]
  35. SMITH C. A. TESTING FOR HETEROGENEITY OF RECOMBINATION FRACTION VALUES IN HUMAN GENETICS. Ann Hum Genet. 1963 Nov;27:175–182. doi: 10.1111/j.1469-1809.1963.tb00210.x. [DOI] [PubMed] [Google Scholar]
  36. Shultz L. D., Schweitzer P. A., Rajan T. V., Yi T., Ihle J. N., Matthews R. J., Thomas M. L., Beier D. R. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 1993 Jul 2;73(7):1445–1454. doi: 10.1016/0092-8674(93)90369-2. [DOI] [PubMed] [Google Scholar]
  37. Stark B., Cohen I. J., Pecht M., Umiel T., Apte R. N., Friedman E., Levin S., Vogel R., Schlesinger M., Zaizov R. Immunologic dysregulation in a patient with familial hemophagocytic lymphohistiocytosis. Cancer. 1987 Dec 1;60(11):2629–2636. doi: 10.1002/1097-0142(19871201)60:11<2629::aid-cncr2820601110>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  38. Stéphan J. L., Donadieu J., Ledeist F., Blanche S., Griscelli C., Fischer A. Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A. Blood. 1993 Oct 15;82(8):2319–2323. [PubMed] [Google Scholar]
  39. Tabrizi M., Yang W., Jiao H., DeVries E. M., Platanias L. C., Arico M., Yi T. Reduced Tyk2/SHP-1 interaction and lack of SHP-1 mutation in a kindred of familial hemophagocytic lymphohistiocytosis. Leukemia. 1998 Feb;12(2):200–206. doi: 10.1038/sj.leu.2400949. [DOI] [PubMed] [Google Scholar]
  40. Villa A., Santagata S., Bozzi F., Giliani S., Frattini A., Imberti L., Gatta L. B., Ochs H. D., Schwarz K., Notarangelo L. D. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998 May 29;93(5):885–896. doi: 10.1016/s0092-8674(00)81448-8. [DOI] [PubMed] [Google Scholar]
  41. Waterhouse P., Penninger J. M., Timms E., Wakeham A., Shahinian A., Lee K. P., Thompson C. B., Griesser H., Mak T. W. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995 Nov 10;270(5238):985–988. doi: 10.1126/science.270.5238.985. [DOI] [PubMed] [Google Scholar]
  42. Weissenbach J., Gyapay G., Dib C., Vignal A., Morissette J., Millasseau P., Vaysseix G., Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. doi: 10.1038/359794a0. [DOI] [PubMed] [Google Scholar]

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