Journal of Inherited Metabolic Disease

, Volume 34, Issue 1, pp 121–126

LMBRD1: the gene for the cblF defect of vitamin B12 metabolism

  • Frank Rutsch
  • Susann Gailus
  • Terttu Suormala
  • Brian Fowler
Homocysteine and B-Vitamin Metabolism

Abstract

To date, only very few genetic disorders due to defects in lysosomal membrane transport are known. This paper reviews the identification of the underlying molecular defect causing an intriguing inborn error of vitamin B12 metabolism, namely, defective lysosomal release of vitamin B12 (cblF defect). Using microcell-mediated chromosome transfer of wild-type human chromosomes into immortalized fibroblasts from a cblF patient and genome-wide homozygosity mapping in 12 unrelated cblF patients, we identified LMBRD1 as a positional candidate gene on chromosome 6q13. Five different frameshift mutations leading to loss of function of both LMBRD1 alleles were detected in the affected patients. Transfection of the LMBRD1 wild-type construct into fibroblasts derived from cblF patients restored cobalamin coenzyme synthesis and function. LMBRD1 encodes a novel lysosomal membrane protein with significant homology to lipocalin membrane receptors. These studies give further insight into the intracellular transport of vitamins, challenge the views on lipocalin receptors, and add to our understanding of lysosomal diseases.

List of abbreviations

Adocbl

Deoxyadenosylcobalamin

OHcbl

Hydroxocobalamin

LMBRD1, LMBD1

LMBR1 domain containing 1

LMBR

Limb region 1

LIMR

Lipocalin-interacting membrane receptor

Mecbl

Methylcobalamin

References

  1. Abecasis GR, Wigginton JE (2005) Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 77:754–767CrossRefPubMedGoogle Scholar
  2. Clark RM, Marker PC, Kingsley DM (2000) A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of hemimelic extra-toes mutant mice. Genomics 67:19–27CrossRefPubMedGoogle Scholar
  3. Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, Baumgartner MR, Fowler B (2008) Gene Identification for the CblD Defect of Vitamin B12 Metabolism. N Engl J Med 358:1454–1464CrossRefPubMedGoogle Scholar
  4. Crisponi L, Crisponi G, Meloni A et al (2007) Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to cold-induced sweating syndrome type 1. Am J Hum Genet 80:971–981CrossRefPubMedGoogle Scholar
  5. Cuthbert AP, Trott DA, Ekong RM et al (1995) Construction and characterization of a highly stable human: rodent monochromosomal hybrid panel for genetic complementation and genome mapping studies. Cytogenet Cell Genet 71:68–76CrossRefPubMedGoogle Scholar
  6. Dufour E, Marden MC, Haertlé T (1990) Beta-lactoglobulin binds retinol and protoporphyrin IX at two different binding sites. FEBS Lett 277:223–226CrossRefPubMedGoogle Scholar
  7. Flower DR (1996) The lipocalin protein family: structure and function. Biochem J 318:1–14PubMedGoogle Scholar
  8. Fluckinger M, Merschak P, Hermann M, Haertle T, Redl B (2008) Lipocalin-Interacting-Membrane-Receptor (Limr) Mediates cellular internalization of beta-lactoglobulin. Biochim Biophys Acta 1778:342–347CrossRefPubMedGoogle Scholar
  9. Gahl WA, Thoene JG, Schneider JA (2002) Cystinosis. N Engl J Med 347:111–121CrossRefPubMedGoogle Scholar
  10. Gailus S, Suormala T, Malerczyk-Aktas AG et al (2010) A novel mutation in LMBRD1 causes the cblF defect of vitamin B12 metabolism in a Turkish patient. J Inherit Metab Dis 33:17–24CrossRefPubMedGoogle Scholar
  11. Idriss JM, Jonas AJ (1991) Vitamin B12 transport by rat liver lysosomal membrane vesicles. J Biol Chem 266:9438–9441PubMedGoogle Scholar
  12. Kastner-Koller U, Deimann P, Konrad C, Steinbauer B (2004) The enhancement of development at nursery school age. Prax Kinderpsychol Kinderpsychiatr 53:145–166PubMedGoogle Scholar
  13. Lettice LA, Horikoshi T, Heaney SJ et al (2002) Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci U S A 99:7548–7553CrossRefPubMedGoogle Scholar
  14. Quadros EV, Nakayama Y, Sequeira JM (2009) The protein and the gene encoding the receptor for cellular uptake of transcobalamin-bound cobalamin. Blood 113:186–192CrossRefPubMedGoogle Scholar
  15. Rosenblatt DS, Hosack A, Matiaszuk NV, Cooper BA, Laframboise R (1985) Defect in vitamin B12 release from lysosomes: newly described inborn error of vitamin B12 metabolism. Science 228(4705):1319–1321CrossRefPubMedGoogle Scholar
  16. Rutsch F, Gailus S, Miousse IR et al (2009) Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B(12) metabolism. Nat Genet 41:234–239CrossRefPubMedGoogle Scholar
  17. Sagné C, Gasnier B (2008) Molecular physiology and pathophysiology of lysosomal membrane transporters. J Inherit Metab Dis 31:258–266CrossRefGoogle Scholar
  18. Suormala T, Baumgartner MR, Coelho D et al (2004) The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem 279:42742–42749CrossRefPubMedGoogle Scholar
  19. Vassiliadis A, Rosenblatt DS, Cooper BA, Bergeron JJ (1991) Lysosomal cobalamin accumulation in fibroblasts from a patient with an inborn error of cobalamin metabolism (CblF Complementation Group): visualization by electron microscope radioautography. Exp Cell Res 195:295–302CrossRefPubMedGoogle Scholar
  20. Wang YH, Chang SC, Huang C, Li YP, Lee CH, Chang MF (2005) Novel nuclear export signal-interacting protein, NESI, critical for the assembly of hepatitis delta virus. J Virol 79:8113–8120CrossRefPubMedGoogle Scholar
  21. Whitehead VM, Rosenblatt RD, Cooper BA (1998) Megaloblastic anemia. In: Nathan DG, Orkin SH (eds) Nathan and Oski’s hematology of infancy and childhood. WB Saunders Company, Philadelphia, pp 385–422Google Scholar
  22. Wojnar P, Lechner M, Merschak P, Redl B (2001) Molecular cloning of a novel lipocalin-1 interacting human cell membrane receptor using phage display. J Biol Chem 276:20206–20212CrossRefPubMedGoogle Scholar
  23. Wojnar P, Lechner M, Redl B (2003) Antisense down-regulation of lipocalin-interacting membrane receptor expression inhibits cellular internalization of lipocalin-1 in human Nt2 cells. J Biol Chem 278:16209–16215CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Frank Rutsch
    • 1
    • 3
  • Susann Gailus
    • 1
  • Terttu Suormala
    • 2
  • Brian Fowler
    • 2
  1. 1.Department of General PediatricsMünster University Children’s HospitalMünsterGermany
  2. 2.Metabolic UnitUniversity Children’s HospitalBaselSwitzerland
  3. 3.Klinik und Poliklinik für Kinder- und Jugendmedizin, Allgemeine PädiatrieUniversitätsklinikum MünsterMünsterGermany

Personalised recommendations