{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMMAA is the gene product responsible for the cblA form of vitamin B₁₂‐responsive methylmalonic aciduria. Early studies cloned the MMAA gene and demonstrated that it encodes a mitochondrial protein of approximately 418 amino acids that contains a conserved AAA ATPase domain. This protein is thought to facilitate the translocation of cobalamin (vitamin B₁₂) into mitochondria, where it is converted into adenosylcobalamin (AdoCbl), the essential cofactor for methylmalonyl‐CoA mutase (MCM) activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical and structural analyses have revealed that MMAA exhibits intrinsic GTPase activity and directly interacts with MCM. This interaction is nucleotide‐selective and occurs preferentially when the mutase is in its inactive (apo) state. MMAA functions in a dual capacity: first, it acts as a “protector” of MCM by preventing inactivation due to the oxidation or damage of its AdoCbl cofactor, and second, it serves as a reactivator by promoting the exchange of a damaged cofactor for a new one in a GTP‐dependent manner. These findings support a molecular “gatekeeping” role for MMAA during the assembly of active MCM."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe clinical relevance of MMAA’s functions is underscored by a series of mutation and phenotype analyses in affected patients. Mutations in MMAA disrupt its ability to properly direct AdoCbl assembly into MCM, thereby compromising enzymatic activity and leading to metabolic derangements seen in methylmalonic aciduria. Detailed studies have identified both novel and recurrent mutations with significant impacts on enzyme stability and protein–protein interactions. Moreover, patient cohort investigations correlate defective MMAA function with more severe biochemical and clinical outcomes, highlighting its essential role in maintaining vitamin B₁₂ homeostasis and overall metabolic integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "C Melissa Dobson, Timothy Wai, Daniel Leclerc, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.242614799"}], "href": "https://doi.org/10.1073/pnas.242614799"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12438653"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12438653"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Fatemeh Keyfi, Mohammad Reza Abbaszadegan, Arndt Rolfs, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Biol Lett (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s11658-016-0005-1"}], "href": "https://doi.org/10.1186/s11658-016-0005-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28536607"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28536607"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xue Yang, Osamu Sakamoto, Yoichi Matsubara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B(12)-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2004.05.002"}], "href": "https://doi.org/10.1016/j.ymgme.2004.05.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15308131"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15308131"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "D Sean Froese, Grazyna Kochan, João R C Muniz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.177717"}], "href": "https://doi.org/10.1074/jbc.M110.177717"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20876572"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20876572"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Tóshiko Takahashi-Íñiguez, Humberto García-Arellano, Mauricio A Trujillo-Roldán, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2010.11.141"}], "href": "https://doi.org/10.1016/j.bbrc.2010.11.141"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21138732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21138732"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Toshiko Takahashi-Iñiguez, Alfonso González-Noriega, Colette Michalak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA mutase activity through their complex formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochimie (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biochi.2017.09.012"}], "href": "https://doi.org/10.1016/j.biochi.2017.09.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28943303"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28943303"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Friederike Hörster, Matthias R Baumgartner, Caroline Viardot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1203/PDR.0b013e3180a0325f"}], "href": "https://doi.org/10.1203/PDR.0b013e3180a0325f"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17597648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17597648"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jordan P Lerner-Ellis, C Melissa Dobson, Timothy Wai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.20104"}], "href": "https://doi.org/10.1002/humu.20104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15523652"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15523652"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "B Merinero, B Pérez, C Pérez-Cerdá, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10545-007-0667-y"}], "href": "https://doi.org/10.1007/s10545-007-0667-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17957493"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17957493"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Laura Dempsey-Nunez, Margaret L Illson, Jana Kent, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High resolution melting analysis of the MMAA gene in patients with cblA and in those with undiagnosed methylmalonic aciduria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2012.09.012"}], "href": "https://doi.org/10.1016/j.ymgme.2012.09.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23026888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23026888"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yiming Lin, Chunmei Lin, Weihua Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mild clinical features of isolated methylmalonic acidemia associated with a novel variant in the MMAA gene in two Chinese siblings."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12881-018-0635-4"}], "href": "https://doi.org/10.1186/s12881-018-0635-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29996803"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29996803"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Rachel S Honjo, Erasmo B Casella, Maria A Vieira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Spondylocostal dysostosis associated with methylmalonic aciduria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Test Mol Biomarkers (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/gtmb.2008.0069"}], "href": "https://doi.org/10.1089/gtmb.2008.0069"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19371216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19371216"}]}]}]}