Abstract

AIM To investigate genetic heterogeneity within the cblA class of inborn error of cobalamin metabolism.

CONTEXT ThecblA disorder is characterised by vitamin B12 (cobalamin) responsive methylmalonic aciduria and deficient synthesis of adenosylcobalamin, required for activity of the mitochondrial enzyme methylmalonyl CoA mutase. ThecblA gene has not been identified or cloned. We have previously described a patient with the clinical and biochemical phenotype of the cblA disorder whose fibroblasts complemented cells from patients with all known types of inborn error of adenosylcobalamin synthesis, includingcblA.

METHODS We have performed somatic cell complementation analysis of the cblAvariant fibroblast line with a panel of 28cblA lines. We have also performed detailed complementation analysis on a panel of 10cblA fibroblast lines, not including thecblA variant line.

RESULTS ThecblA variant line complemented all 28 cell lines of the panel. There was evidence for interallelic complementation among the 10 cblA lines used for detailed complementation analysis; no cell line in this panel complemented all other members.

CONCLUSIONS These results strongly suggest that the cblA variant represents a novel complementation class, which we have designatedcblH and which represents a mutation at a distinct gene. They also suggest that thecblA gene encodes a protein that functions as a multimer, allowing for extensive interallelic complementation.