Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2005 Jul;42(7):551–557. doi: 10.1136/jmg.2005.030759

Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome)

P Ferguson 1, S Chen 1, M Tayeh 1, L Ochoa 1, S Leal 1, A Pelet 1, A Munnich 1, S Lyonnet 1, H Majeed 1, H El-Shanti 1
PMCID: PMC1736104  PMID: 15994876

Abstract

Background: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation.

Methods: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out.

Results: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown.

Conclusions: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.

Full Text

The Full Text of this article is available as a PDF (131.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arndt J. H. Sweet's syndrome and chronic recurrent multifocal osteomyelitis. Am J Dis Child. 1987 Jul;141(7):721–721. doi: 10.1001/archpedi.1987.04460070023009. [DOI] [PubMed] [Google Scholar]
  2. Asumalahti Kati, Laitinen Tarja, Lahermo Päivi, Suomela Sari, Itkonen-Vatjus Raija, Jansen Christer, Karvonen Jaakko, Karvonen Seija-Liisa, Reunala Timo, Snellman Erna. Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1. J Invest Dermatol. 2003 Oct;121(4):735–740. doi: 10.1046/j.1523-1747.2003.12483.x. [DOI] [PubMed] [Google Scholar]
  3. Bassam B. J., Caetano-Anollés G., Gresshoff P. M. Fast and sensitive silver staining of DNA in polyacrylamide gels. Anal Biochem. 1991 Jul;196(1):80–83. doi: 10.1016/0003-2697(91)90120-i. [DOI] [PubMed] [Google Scholar]
  4. Ben Becher S., Essaddam H., Nahali N., Ben Hamadi F., Mouelhi M. H., Hammou A., Hadj Romdhane L., Ben Cheikh M., Boudhina T., Dargouth M. La périostose multifocale récurrente de l'enfant. A propos d'une forme familiale. Ann Pediatr (Paris) 1991 May;38(5):345–349. [PubMed] [Google Scholar]
  5. Bergdahl K., Björkstén B., Gustavson K. H., Lidén S., Probst F. Pustulosis palmoplantaris and its relation to chronic recurrent multifocal osteomyelitis. Dermatologica. 1979;159(1):37–45. doi: 10.1159/000250559. [DOI] [PubMed] [Google Scholar]
  6. Broman K. W., Murray J. C., Sheffield V. C., White R. L., Weber J. L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998 Sep;63(3):861–869. doi: 10.1086/302011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Byrd L., Grossmann M., Potter M., Shen-Ong G. L. Chronic multifocal osteomyelitis, a new recessive mutation on chromosome 18 of the mouse. Genomics. 1991 Dec;11(4):794–798. doi: 10.1016/0888-7543(91)90002-v. [DOI] [PubMed] [Google Scholar]
  8. Cann Howard M., de Toma Claudia, Cazes Lucien, Legrand Marie-Fernande, Morel Valerie, Piouffre Laurence, Bodmer Julia, Bodmer Walter F., Bonne-Tamir Batsheva, Cambon-Thomsen Anne. A human genome diversity cell line panel. Science. 2002 Apr 12;296(5566):261–262. doi: 10.1126/science.296.5566.261b. [DOI] [PubMed] [Google Scholar]
  9. Cao Henian, Hegele Robert A. Identification of single-nucleotide polymorphisms in the human LPIN1 gene. J Hum Genet. 2002;47(7):370–372. doi: 10.1007/s100380200052. [DOI] [PubMed] [Google Scholar]
  10. Cohen Jonathan C., Kiss Robert S., Pertsemlidis Alexander, Marcel Yves L., McPherson Ruth, Hobbs Helen H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science. 2004 Aug 6;305(5685):869–872. doi: 10.1126/science.1099870. [DOI] [PubMed] [Google Scholar]
  11. Edwards T. C., Stapleton F. B., Bond M. J., Barrett F. F. Sweet's syndrome with multifocal sterile osteomyelitis. Am J Dis Child. 1986 Aug;140(8):817–818. doi: 10.1001/archpedi.1986.02140220099042. [DOI] [PubMed] [Google Scholar]
  12. Festen J. J., Kuipers F. C., Schaars A. H. Multifocal recurrent periostitis responsive to colchicine. Scand J Rheumatol. 1985;14(1):8–14. doi: 10.3109/03009748509102009. [DOI] [PubMed] [Google Scholar]
  13. Giedion A., Holthusen W., Masel L. F., Vischer D. [Subacute and chronic "symmetrical" osteomyelitis]. Ann Radiol (Paris) 1972 Mar-Apr;15(3):329–342. [PubMed] [Google Scholar]
  14. Golla Astrid, Jansson Annette, Ramser Juliane, Hellebrand Heide, Zahn Robert, Meitinger Thomas, Belohradsky Bernd H., Meindl Alfons. Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3-18q22. Eur J Hum Genet. 2002 Mar;10(3):217–221. doi: 10.1038/sj.ejhg.5200789. [DOI] [PubMed] [Google Scholar]
  15. Hentunen T. A., Choi S. J., Boyce B. F., Dallas M. R., Dallas S. L., Shen-Ong G. L., Roodman G. D. A murine model of inflammatory bone disease. Bone. 2000 Feb;26(2):183–188. doi: 10.1016/s8756-3282(99)00247-1. [DOI] [PubMed] [Google Scholar]
  16. Job-Deslandre C., Krebs S., Kahan A. Chronic recurrent multifocal osteomyelitis: five-year outcomes in 14 pediatric cases. Joint Bone Spine. 2001 May;68(3):245–251. doi: 10.1016/s1297-319x(01)00276-7. [DOI] [PubMed] [Google Scholar]
  17. Keipert J. A., Campbell P. E. Recurrent hyperostosis of the clavicles: an undiagnosed syndrome. Aust Paediatr J. 1970 Mar;6(1):97–104. [PubMed] [Google Scholar]
  18. Khoury S. A., Massad D. F. Consanguinity, fertility, reproductive wastage, infant mortality and congenital malformations in Jordan. Saudi Med J. 2000 Feb;21(2):150–154. [PubMed] [Google Scholar]
  19. Khoury S. A., Massad D. Consanguineous marriage in Jordan. Am J Med Genet. 1992 Jul 15;43(5):769–775. doi: 10.1002/ajmg.1320430502. [DOI] [PubMed] [Google Scholar]
  20. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985 May;37(3):482–498. [PMC free article] [PubMed] [Google Scholar]
  21. Laxer R. M., Shore A. D., Manson D., King S., Silverman E. D., Wilmot D. M. Chronic recurrent multifocal osteomyelitis and psoriasis--a report of a new association and review of related disorders. Semin Arthritis Rheum. 1988 May;17(4):260–270. doi: 10.1016/0049-0172(88)90011-x. [DOI] [PubMed] [Google Scholar]
  22. Majeed H. A., Al-Tarawna M., El-Shanti H., Kamel B., Al-Khalaileh F. The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr. 2001 Dec;160(12):705–710. doi: 10.1007/s004310100799. [DOI] [PubMed] [Google Scholar]
  23. Majeed H. A., El-Shanti H., Al-Rimawi H., Al-Masri N. On mice and men: An autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr. 2000 Sep;137(3):441–442. doi: 10.1067/mpd.2000.107613. [DOI] [PubMed] [Google Scholar]
  24. Majeed H. A., Kalaawi M., Mohanty D., Teebi A. S., Tunjekar M. F., al-Gharbawy F., Majeed S. A., al-Gazzar A. H. Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr. 1989 Nov;115(5 Pt 1):730–734. doi: 10.1016/s0022-3476(89)80650-x. [DOI] [PubMed] [Google Scholar]
  25. Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O., Tanaka A., Kotani H., Miyajima N., Nomura N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 1996 Oct 31;3(5):321-9, 341-54. doi: 10.1093/dnares/3.5.321. [DOI] [PubMed] [Google Scholar]
  26. Nurre L. D., Rabalais G. P., Callen J. P. Neutrophilic dermatosis-associated sterile chronic multifocal osteomyelitis in pediatric patients: case report and review. Pediatr Dermatol. 1999 May-Jun;16(3):214–216. doi: 10.1046/j.1525-1470.1999.00058.x. [DOI] [PubMed] [Google Scholar]
  27. Paller A. S., Pachman L., Rich K., Esterly N. B., Gonzalez-Crussi F. Pustulosis palmaris et plantaris: its association with chronic recurrent multifocal osteomyelitis. J Am Acad Dermatol. 1985 May;12(5 Pt 2):927–930. doi: 10.1016/s0190-9622(85)70115-6. [DOI] [PubMed] [Google Scholar]
  28. Prose N. S., Fahrner L. J., Miller C. R., Layfield L. Pustular psoriasis with chronic recurrent multifocal osteomyelitis and spontaneous fractures. J Am Acad Dermatol. 1994 Aug;31(2 Pt 2):376–379. doi: 10.1016/s0190-9622(94)70176-8. [DOI] [PubMed] [Google Scholar]
  29. Péterfy M., Phan J., Xu P., Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet. 2001 Jan;27(1):121–124. doi: 10.1038/83685. [DOI] [PubMed] [Google Scholar]
  30. Sakran Waheeb, Lumelsky Dmitry, Schildkraut Vered, Smolkin Vladislav, Halevy Raphael, Koren Ariel. Chronic recurrent multifocal osteomyelitis in infancy: a case report. Clin Pediatr (Phila) 2003 Oct;42(8):741–744. doi: 10.1177/000992280304200810. [DOI] [PubMed] [Google Scholar]
  31. Sobel E., Lange K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet. 1996 Jun;58(6):1323–1337. [PMC free article] [PubMed] [Google Scholar]
  32. Tange Yoshie, Hirata Aiko, Niwa Osami. An evolutionarily conserved fission yeast protein, Ned1, implicated in normal nuclear morphology and chromosome stability, interacts with Dis3, Pim1/RCC1 and an essential nucleoporin. J Cell Sci. 2002 Nov 15;115(Pt 22):4375–4385. doi: 10.1242/jcs.00135. [DOI] [PubMed] [Google Scholar]
  33. Vermylen C., Scheiff J. M., Rodhain J., Ninane J., Cornu G. A variant of the congenital dyserythropoietic anaemia type II with structural abnormalities in the granulocytic series. Eur J Pediatr. 1986 Aug;145(3):232–235. doi: 10.1007/BF00446076. [DOI] [PubMed] [Google Scholar]
  34. Vittecoq O., Said L. A., Michot C., Mejjad O., Thomine J. M., Mitrofanoff P., Lechevallier J., Ledosseur P., Gayet A., Lauret P. Evolution of chronic recurrent multifocal osteitis toward spondylarthropathy over the long term. Arthritis Rheum. 2000 Jan;43(1):109–119. doi: 10.1002/1529-0131(200001)43:1<109::AID-ANR14>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  35. Weeks D. E., Sobel E., O'Connell J. R., Lange K. Computer programs for multilocus haplotyping of general pedigrees. Am J Hum Genet. 1995 Jun;56(6):1506–1507. [PMC free article] [PubMed] [Google Scholar]
  36. Young T. L., Ives E., Lynch E., Person R., Snook S., MacLaren L., Cater T., Griffin A., Fernandez B., Lee M. K. Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum Mol Genet. 2001 Oct 15;10(22):2509–2514. doi: 10.1093/hmg/10.22.2509. [DOI] [PubMed] [Google Scholar]
  37. Zucchero Theresa M., Cooper Margaret E., Maher Brion S., Daack-Hirsch Sandra, Nepomuceno Buena, Ribeiro Lucilene, Caprau Diana, Christensen Kaare, Suzuki Yasushi, Machida Junichiro. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004 Aug 19;351(8):769–780. doi: 10.1056/NEJMoa032909. [DOI] [PubMed] [Google Scholar]
  38. al-Salem M., Rawashdeh N. Consanguinity in north Jordan: prevalence and pattern. J Biosoc Sci. 1993 Oct;25(4):553–556. doi: 10.1017/s0021932000021921. [DOI] [PubMed] [Google Scholar]
  39. el-Shanti H., Murray J. C., Semina E. V., Beutow K. H., Scherpbier T., al-Alami J. Assignment of gene responsible for progressive pseudorheumatoid dysplasia to chromosome 6 and examination of COL10A1 as candidate gene. Eur J Hum Genet. 1998 May-Jun;6(3):251–256. doi: 10.1038/sj.ejhg.5200187. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

[Web-only table]
jmedgene_42_7_551__index.html (1.3KB, html)
jmedgene_42_7_551__1.pdf (58.3KB, pdf)

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES