Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant.

Autor: Paz D; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Pinales BE; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Castellanos BS; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Perez I; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Gil CB; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Madrigal LJ; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Reyes-Nava NG; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Castro VL; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA., Sloan JL; Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Quintana AM; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA. Electronic address: aquintana8@utep.edu.
Jazyk: angličtina
Zdroj: Differentiation; research in biological diversity [Differentiation] 2023 May-Jun; Vol. 131, pp. 74-81. Date of Electronic Publication: 2023 May 05.
DOI: 10.1016/j.diff.2023.04.003
Abstrakt: Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes 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 cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in MMACHC cause 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 MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.
Competing Interests: Declaration of competing interest Authors have no conflicts of interests to declare.
(Copyright © 2023 International Society of Differentiation. All rights reserved.)
Databáze: MEDLINE
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