LMBRD1 – Methylmalonic Aciduria and Homocystinuria Type cblF

LMBRD1-related cblF defect is an autosomal recessive disorder characterized by impaired lysosomal export of cobalamin leading to combined methylmalonic aciduria and homocystinuria (MONDO_0010183). LMBRD1 encodes LMBD1, a lysosomal membrane protein essential for cobalamin release into the cytoplasm. Clinical detection often follows newborn screening for elevated propionyl carnitine, and affected individuals present with multi-system involvement. Here we integrate genetic, clinical, and functional evidence supporting a strong gene–disease association.

Autosomal recessive inheritance is confirmed by homozygosity mapping in 12 unrelated cblF patients, localizing the defect to chromosome 6q13 and implicating LMBRD1 ([PMID:20446115]). To date, at least 14 probands have been reported with bi-allelic pathogenic LMBRD1 variants ([PMID:22065268]). The variant spectrum comprises loss-of-function alleles: frameshifts (e.g., c.1056del (p.Leu352fsTer18)), splice site mutations (c.916-1G>T, c.1339-1G>T), and multi-exonic deletions. A recurrent founder variant c.1056del (p.Leu352fsTer18) accounts for 18 of 24 disease chromosomes ([PMID:19136951]). No large copy-number variants have been described.

Phenotypic manifestations include small for gestational age, dysmorphic features, trigonocephaly, and ventricular septal defect in early life ([PMID:22065268]). Additional signs are failure to thrive, hypotonia, seizures, intellectual disability, skin rash, and megaloblastic anemia ([PMID:21910240]). Developmental delays vary with treatment regimen; weekly hydroxocobalamin typically normalizes metabolites without metabolic crises. Cardiac anomalies and growth failure may persist despite therapy.

Functional assays provide moderate evidence for a loss-of-function mechanism. Patient fibroblasts transfected with wild-type LMBRD1 restore cobalamin coenzyme synthesis and metabolic function ([PMID:19136951]). Microcell-mediated chromosome transfer or LMBD1 cDNA complementation similarly rescues deficient fibroblasts ([PMID:20446115]). Lmbrd1 knockout mice exhibit early embryonic lethality, confirming an essential developmental role ([PMID:27061115]). These data support homozygous loss as the pathogenic mechanism.

Mechanistic studies reveal that LMBD1 interacts with the ABC transporter ABCD4 to mediate lysosomal-to-cytosolic cobalamin export. In vitro binding and live-cell assays demonstrate that LMBD1–ABCD4 complexes exhibit low nanomolar affinity, and ABCD4 fails to localize to lysosomes in LMBRD1-deficient cells ([PMID:25535791], [PMID:27456980]). Disruption of this interaction underlies cobalamin cofactor deficiency.

Together, robust genetic and functional data support a Strong clinical validity classification for LMBRD1 in cblF disease. Genetic evidence includes 14 unrelated probands, homozygosity mapping in 12 families, and a common founder frameshift. Functional rescue in patient cells and embryonic lethality in mouse models confirm loss-of-function. This consolidated evidence guides diagnostic sequencing, carrier screening, and informs parenteral cobalamin therapy. Key take-home: LMBRD1 mutations cause treatable autosomal recessive cblF disease, underscoring the importance of early molecular diagnosis.

References

• Journal of inherited metabolic disease • 2011 • LMBRD1: the gene for the cblF defect of vitamin B₁₂ metabolism PMID:20446115
• Pediatrics • 2011 • Cobalamin F disease detected by newborn screening and follow-up on a 14-year-old patient. PMID:22065268
• Nature genetics • 2009 • Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B₁₂ metabolism. PMID:19136951
• American journal of medical genetics. Part A • 2011 • Eighteen-year follow-up of a patient with cobalamin F disease (cblF): report and review. PMID:21910240
• Journal of cellular and molecular medicine • 2016 • Lmbrd1 expression is essential for the initiation of gastrulation. PMID:27061115
• Molecular membrane biology • 2014 • Purification and interaction analyses of two human lysosomal vitamin B₁₂ transporters: LMBD1 and ABCD4. PMID:25535791
• Scientific reports • 2016 • Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1. PMID:27456980

Evidence Based Scoring (AI generated)