| Popis: |
Variants in theMMACHCgene cause combined methylmalonic acidemia and homocystinuriacblCtype, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism.cblCis associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models ofMmachcdeletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts.MMACHCencodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such ascblXsyndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation incblXsyndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutation ofMMACHCcause craniofacial defects have not been completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model ofcblC(hg13) and performed restoration experiments with either wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development, but did have abnormal chondrocyte intercalation, which was fully penetrant. Abnormal chondrocyte intercalation was not associated with defects in the expression/localization of neural crest specific markers,sox10orbarx1. Most importantly, chondrocyte organization was fully restored by wildtype MMACHC and a cobalamin binding deficient variant of MMACHC protein. Collectively, these data suggest that mutation ofMMACHCcauses mild to moderate craniofacial phenotypes that are independent of cobalamin binding. |
