<i>LMBRD1</i>: the gene for the cblF defect of vitamin B<sub>12</sub> metabolism

Rutsch, Frank; Gailus, Susann; Suormala, Terttu; Fowler, Brian

doi:10.1007/s10545-010-9083-9

Cited by 33 publications

(20 citation statements)

References 21 publications

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“…The identified alterations are likely founder mutations among individuals of European ancestry, consistent with the family's reported ancestry (Watkins et al 2002;Rutsch et al 2011). MTR and LMBRD1 are two of the several proteins essential to cobalamin metabolism (reviewed in Sarafoglou and Hoffman 2009;Watkins and Rosenblatt 2011).…”

Section: Discussionsupporting

confidence: 67%

“…c.3518C>T (p.P1173L) is the most common alteration observed in the MTR gene, with a frequency of about 40% (16/38 chromosomes) of patients with cblG deficiency (Watkins et al 2002). LMBRD1 c.1056delG (p.L352Lfs*18) is the most frequently reported alteration, found to be present in 75% (18/24 chromosomes) of one cohort of 12 patients with cblF deficiency (Rutsch et al 2009(Rutsch et al , 2011.…”

Section: Discussionmentioning

confidence: 97%

“…Other clinical findings in patients with cblG include decreased S-adenosylmethionine, lethargy, feeding difficulties, vomiting, abnormal tonus, mental retardation, failure to thrive, blindness, ataxia, delayed myelination, and megaloblastic anemia (Sarafoglou and Hoffman 2009). LMBRD1 is a lysosomal membrane protein thought to be involved in lysosomal export of cobalamin in which alteration leads to the cblF complementation class of the cobalamin metabolism disorders (Rutsch et al 2009(Rutsch et al , 2011Gailus et al 2010). Cells from cblF patients accumulate large amounts of free cobalamin within the lysosomes, but there is a deficiency of both cobalamin coenzyme derivatives and decreased activity of MMA mutase and methionine sythetase (reviewed in Watkins and Rosenblatt, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Cells from cblF patients accumulate large amounts of free cobalamin within the lysosomes, but there is a deficiency of both cobalamin coenzyme derivatives and decreased activity of MMA mutase and methionine sythetase (reviewed in Watkins and Rosenblatt, 2011). Immortalized fibroblasts from patients with cblF show restored cobalamin coenzyme synthesis and function upon transfection with an LMBRD1 wild-type complementary DNA (cDNA) construct (Rutsch et al 2011). Typical clinical findings in patients with cblF are evident by the first year of life and include increased homocystine and MMA, encephalopathy, poor head growth, decreased cobalamin levels, mental retardation, ataxia, and megaloblastic anemia and/or pancytopenia (Sarafoglou and Hoffman 2009).…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes

González

et al. 2014

JIMD Reports

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Disorders of cobalamin deficiency are a heterogeneous group of disorders with at least 19 autosomal recessive-associated genes. Familial samples of an infant who died due to presumed cobalamin deficiency were referred for clinical exome sequencing. The patient died before obtaining a blood sample or skin biopsy, autopsy was declined, and DNA yielded from the newborn screening blood spot was insufficient for diagnostic testing. Whole-exome sequencing of the mother, father, and unaffected sister and tailored bioinformatics analysis was applied to search for mutations in underlying disorders with recessive inheritance. This approach identified alterations within two genes, each of which was carried by one parent. The mother carried a missense alteration in the MTR gene (c.3518C>T; p.P1173L) which was absent in the father and the sister. The father carried a translational frameshift alteration in the LMBRD1 gene (c.1056delG; p.L352Lfs*18) which was absent in the mother and present in the heterozygous state in the sister. These mutations in the MTR (MIM# 156570) and LMBRD1 (MIM# 612625) genes have been described in patients with disorders of cobalamin metabolism complementation groups cblG and cblF, respectively. The child's clinical presentation and biochemical results demonstrated overlap with both cblG and cblF. Sanger sequencing using DNA from the infant's blood spot confirmed the inheritance of the two alterations in compound heterozygous form. We present the first example of exome sequencing leading to a diagnosis in the absence of the affected patient. Furthermore, the data support the possibility for potential digenic inheritance associated with cobalamin deficiency.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes

González

et al. 2014

JIMD Reports

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“…Cells take up holo-TC via receptor-mediated endocytosis, aided by the transcobalamin receptor (CD320), 45,46 which shuttles vitamin B 12 into lysosomes. The protein binder TC undergoes degradation in the lysosome, liberating vitamin B 12 that is subsequently exported out of this compartment using the transporters LMBR1 Domain Containing 1 (LMBRD1) 47,48 and ATP Binding Cassette Subfamily D Member 4 (ABCD4). 49,50 Once in the cytosol, newly internalized vitamin B 12 undergoes processing and trafficking by proteins, CblC [51][52][53][54][55][56][57] and CblD, [58][59][60][61][62][63] respectively, to finally reach acceptor proteins, MS in the cytosol and MCM in the mitochondrion.…”

Section: Vitamin B 12 Metabolismmentioning

confidence: 99%

Hampered Vitamin B12 Metabolism in Gaucher Disease?

Hannibal

Siebert

Basgalupp

et al. 2017

Journal of Inborn Errors of Metabolism and Screening

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Untreated vitamin B 12 deficiency manifests clinically with hematological abnormalities and combined degeneration of the spinal cord and polyneuropathy and biochemically with elevated homocysteine (Hcy) and methylmalonic acid (MMA). Vitamin B 12 metabolism involves various cellular compartments including the lysosome, and a disruption in the lysosomal and endocytic pathways induces functional deficiency of this micronutrient. Gaucher disease (GD) is characterized by dysfunctional lysosomal metabolism brought about by mutations in the enzyme beta-glucocerebrosidase (Online Mendelian Inheritance in Man (OMIM): 606463; Enzyme Commission (EC) 3.2.1.45, gene: GBA1). In this study, we collected and examined available literature on the associations between GD, the second most prevalent lysosomal storage disorder in humans, and hampered vitamin B 12 metabolism. Results from independent cohorts of patients show elevated circulating holotranscobalamin without changes in vitamin B 12 levels in serum. Gaucher disease patients under enzyme replacement therapy present normal levels of Hcy and MMA. Although within the normal range, a significant increase in Hcy and MMA with normal serum vitamin B 12 was documented in treated GD patients with polyneuropathy versus treated GD patients without polyneuropathy. Thus, a functional deficiency of vitamin B 12 caused by disrupted lysosomal metabolism in GD is a plausible mechanism, contributing to the neurological form of the disorder but this awaits confirmation. Observational studies suggest that an assessment of vitamin B 12 status prior to the initiation of enzyme replacement therapy may shed light on the role of vitamin B 12 in the pathogenesis and progression of GD.

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