| Autor: |
Paz, David, Pinales, Briana E., Castellanos, Barbara S., Perez, Isaiah, Gil, Claudia B., Madrigal, Lourdes Jimenez, Reyes-Nava, Nayeli G., Castro, Victoria L., Sloan, Jennifer L., Quintana, Anita M. |
| Zdroj: |
Differentiation; May-June 2023, Vol. 131 Issue: 1 p74-81, 8p |
| Abstrakt: |
Variants in the MMACHCgene cause combined methylmalonic acidemia and homocystinuria cblCtype, 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 of Mmachcdeletion 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 as cblXsyndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblXsyndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in MMACHCcause craniofacial defects are yet to be completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC(hg13) and performed restoration experiments with either a wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development but did have abnormal chondrocyte nuclear organization and an increase in the average number of neighboring cell contacts, both phenotypes were fully penetrant. Abnormal chondrocyte nuclear organization was not associated with defects in the localization of neural crest specific markers, sox10(RFP transgene) or barx1. Both nuclear angles and the number of neighboring cell contacts were fully restored by wildtype MMACHC and a cobalamin binding deficient variant of the MMACHC protein. Collectively, these data suggest that mutation of MMACHCcauses mild to moderate craniofacial phenotypes that are independent of cobalamin binding. |
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