Absence of MMACHC in peripheral retinal cells does not lead to an ocular phenotype in mice

Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

“…To address the pathogenesis of the striking ocular phenotypes in cblC patients, Kiessling et al. generated the first organ- and tissue-specific mouse model ( Kiessling et al., 2021 ). Mmachc flox/flox ; Pax6Cre mice, named retina Δ Mmachc mice, are depleted of Mmachc expression in the peripheral, but not in the central retina, as of embryonic day E10.5.…”

“…Interestingly, two viable Mmachc tm1.1/tm1.1 weanlings were rescued from mothers carrying the overexpressed allele suggesting a maternal-effect rescue as also discussed for the zebrafish model. To address the pathogenesis of the striking ocular phenotypes in cblC patients, Kiessling et al generated the first organ-and tissue-specific mouse model (Kiessling et al, 2021). Mmachc flox/flox ; Pax6Cre mice, named retina DMmachc mice, are depleted of Mmachc expression in the peripheral, but not in the central retina, as of embryonic day E10.5.…”

Investigation on a MMACHC mutant from cblC disease: The c.394C>T variant

“…The disease results in impaired intracellular synthesis of adenosylcobalamin (Ado-Cbl) and methylcobalamin (Me-Cbl), cofactors for the mitochondrial methylmalonyl-CoA mutase (MUT) and cytosolic methionine synthase (MS) enzymes, respectively (1,2). The clinical consequences are devastating and systemic, including pulmonary problems, hemolytic-uremic syndrome, neurocognitive impairment, and degenerative maculopathy (3)(4)(5)(6). The onset may be early (EO) (a few weeks) or late (LO) (second, third decade of life) (7).…”