{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:29:31Z","timestamp":1768505371102,"version":"3.49.0"},"posted":{"date-parts":[[2023,1,21]]},"group-title":"Developmental Biology","reference-count":41,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Variants in the\n                  <jats:italic>MMACHC<\/jats:italic>\n                  gene cause combined methylmalonic acidemia and homocystinuria\n                  <jats:italic>cblC<\/jats:italic>\n                  type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism.\n                  <jats:italic>cblC<\/jats:italic>\n                  is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of\n                  <jats:italic>Mmachc<\/jats:italic>\n                  deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts.\n                  <jats:italic>MMACHC<\/jats:italic>\n                  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\n                  <jats:italic>cblX<\/jats:italic>\n                  syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in\n                  <jats:italic>cblX<\/jats:italic>\n                  syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutation of\n                  <jats:italic>MMACHC<\/jats:italic>\n                  cause craniofacial defects have not been completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of\n                  <jats:italic>cblC<\/jats:italic>\n                  (\n                  <jats:italic>hg13<\/jats:italic>\n                  ) 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,\n                  <jats:italic>sox10<\/jats:italic>\n                  or\n                  <jats:italic>barx1<\/jats:italic>\n                  . 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 of\n                  <jats:italic>MMACHC<\/jats:italic>\n                  causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.\n                <\/jats:p>","DOI":"10.1101\/2023.01.20.524982","type":"posted-content","created":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T06:10:23Z","timestamp":1674281423000},"source":"Crossref","is-referenced-by-count":0,"title":["Abnormal chondrocyte intercalation in a zebrafish model of\n                  <i>cblC<\/i>\n                  syndrome restored by an MMACHC cobalamin binding mutant"],"prefix":"10.64898","author":[{"given":"David","family":"Paz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Briana E.","family":"Pinales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara S.","family":"Castellanos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaiah","family":"Perez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia B.","family":"Gil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lourdes","family":"Jimenez Madrigal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nayeli G.","family":"Reyes-Nava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria L.","family":"Castro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L.","family":"Sloan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-1587","authenticated-orcid":false,"given":"Anita M.","family":"Quintana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023012403300610000_2023.01.20.524982v1.1","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/j.1601-0825.2008.01509.x","article-title":"Enamel defects and salivary methylmalonate in methylmalonic acidemia","volume":"15","year":"2009","journal-title":"Oral Dis"},{"key":"2023012403300610000_2023.01.20.524982v1.2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2001-12217"},{"key":"2023012403300610000_2023.01.20.524982v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22090"},{"key":"2023012403300610000_2023.01.20.524982v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9364-y"},{"key":"2023012403300610000_2023.01.20.524982v1.5","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9364-y"},{"key":"2023012403300610000_2023.01.20.524982v1.6","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1023\/A:1005521702298","article-title":"Minor facial anomalies in combined methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism","volume":"22","year":"1999","journal-title":"J. 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