Journal of Inherited Metabolic Disease

, Volume 33, Issue 1, pp 17–24

A novel mutation in LMBRD1 causes the cblF defect of vitamin B12 metabolism in a Turkish patient

  • Susann Gailus
  • Terttu Suormala
  • Ayse Gül Malerczyk-Aktas
  • Mohammad R. Toliat
  • Tanja Wittkampf
  • Martin Stucki
  • Peter Nürnberg
  • Brian Fowler
  • Julia B. Hennermann
  • Frank Rutsch
Original Article

DOI: 10.1007/s10545-009-9032-7

Cite this article as:
Gailus, S., Suormala, T., Malerczyk-Aktas, A.G. et al. J Inherit Metab Dis (2010) 33: 17. doi:10.1007/s10545-009-9032-7

Abstract

In the cblF defect of vitamin B12 (cobalamin) metabolism, cobalamin is trapped in lysosomes. Consequently, cobalamin coenzyme synthesis is blocked, and cofactors for methionine synthase and methylmalonyl-coenzyme A (CoA) mutase are deficient. We recently identified LMBRD1 as the causative gene located on chromosome 6q13 and showed that 18 out of 24 alleles in unrelated patients carried the deletion c.1056delG (p.L352fsX18) (Rutsch et al. (Nat Genet 41:234–239, 2009). LMBRD1 encodes the lysosomal membrane protein LMBD1, which presumably facilitates lysosomal cobalamin export. Our patient is the second child of consanguineous Turkish parents. He presented on the second day of life with cerebral seizures due to intraventricular hemorrhage. Plasma homocysteine and urinary methylmalonic acid levels were elevated, and serum cobalamin level was decreased. Synthesis of both cobalamin coenzymes was deficient in cultured skin fibroblasts. The cblF defect was confirmed by somatic complementation analysis. Sequencing of LMBRD1 revealed the novel deletion c.1405delG (p.D469fsX38) on both alleles. Real-time polymerase chain reaction (PCR) revealed reduced messenger RNA (mRNA) levels in patient fibroblasts compared with controls. Transfection of patient fibroblasts with the LMBD1 wild-type complement DNA (cDNA) rescued coenzyme synthesis and function, confirming this new deletion as an additional cause of the cblF defect. This case adds to the spectrum of clinical presentations and mutations of this rare disorder of lysosomal transport.

Abbreviations

AdoCbl

Adenosylcobalamin

LMBRD1, LMBD1

LMBR1 domain containing 1

LMBR

limb region 1

LIMR

lipocalin-interacting membrane receptor

MeCbl

Methylcobalamin

Supplementary material

10545_2009_9032_Fig1_ESM.gif (48 kb)
Supplementary Table 1(GIF 48 kb)
10545_2009_9032_Fig2_ESM.gif (152 kb)
Supplementary Table 2(GIF 151 kb)
10545_2009_9032_Fig3_ESM.doc (139 kb)
Supplementary Figure 1(DOC 139 kb)

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Susann Gailus
    • 1
  • Terttu Suormala
    • 2
  • Ayse Gül Malerczyk-Aktas
    • 3
  • Mohammad R. Toliat
    • 5
  • Tanja Wittkampf
    • 1
  • Martin Stucki
    • 6
    • 7
  • Peter Nürnberg
    • 5
    • 8
  • Brian Fowler
    • 2
  • Julia B. Hennermann
    • 4
  • Frank Rutsch
    • 1
    • 9
  1. 1.Department of General PediatricsMünster University Children’s HospitalMünsterGermany
  2. 2.Metabolic UnitUniversity Children’s HospitalBaselSwitzerland
  3. 3.Department of General PediatricsUniversity Hospital of Giessen and MarburgMarburgGermany
  4. 4.Department of PediatricsCharité University Medical CenterBerlinGermany
  5. 5.Cologne Center for Genomics and Institute for GeneticsCologneGermany
  6. 6.Division of Metabolism and Molecular PediatricsUniversity Children’s HospitalZürichSwitzerland
  7. 7.Zürich Center for Integrative Human Physiology (ZIHP)University of ZürichZürichSwitzerland
  8. 8.Cologne Excellence Cluster on Cellular Stress Response in Aging-associated Diseases (CECAD)University of CologneCologneGermany
  9. 9.Klinik und Poliklinik für Kinder- und JugendmedizinUniversitätsklinikum MünsterMünsterGermany