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A novel mutation in LMBRD1 causes the cblF defect of vitamin B 12 metabolism in a Turkish patient
Author(s) -
Gailus Susann,
Suormala Terttu,
MalerczykAktas Ayse Gül,
Toliat Mohammad R.,
Wittkampf Tanja,
Stucki Martin,
Nürnberg Peter,
Fowler Brian,
Hennermann Julia B.,
Rutsch Frank
Publication year - 2010
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-009-9032-7
Subject(s) - cobalamin , biology , microbiology and biotechnology , methylmalonic acid , mutase , complementation , missense mutation , methylmalonic acidemia , methionine synthase , cofactor , vitamin b12 , biochemistry , mutation , methionine , gene , endocrinology , enzyme , amino acid , phenotype
In the cblF defect of vitamin B 12 (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.