{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:54:38Z","timestamp":1781639678842,"version":"3.54.5"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Recon4IMD project"},{"name":"Wellcome Centre for Mitochondrial Research","award":["203105\/Z\/16\/Z"],"award-info":[{"award-number":["203105\/Z\/16\/Z"]}]},{"name":"Medical Research Council","award":["MR\/W019027\/1"],"award-info":[{"award-number":["MR\/W019027\/1"]}]},{"name":"Medical Research Council","award":["MR\/W019027\/1"],"award-info":[{"award-number":["MR\/W019027\/1"]}]},{"name":"Medical Research Council","award":["MR\/W019027\/1"],"award-info":[{"award-number":["MR\/W019027\/1"]}]},{"name":"Royal National Institute for the Deaf\/Masonic Charitable Foundation","award":["S60_Newman"],"award-info":[{"award-number":["S60_Newman"]}]},{"name":"Royal National Institute for the Deaf\/Masonic Charitable Foundation","award":["S60_Newman"],"award-info":[{"award-number":["S60_Newman"]}]},{"DOI":"10.13039\/100014653","name":"NIHR Manchester Biomedical Research Centre","doi-asserted-by":"crossref","award":["NIHR 203308"],"award-info":[{"award-number":["NIHR 203308"]}],"id":[{"id":"10.13039\/100014653","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurogenetics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Biallelic hypomorphic variants in\n                    <jats:italic>PRORP<\/jats:italic>\n                    cause the rare autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a clinical spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy with developmental delay and epilepsy. Here, we report two new affected individuals with biallelic\n                    <jats:italic>PRORP<\/jats:italic>\n                    variants with clinical features consistent with COXPD54. One individual was homozygous for c.1505G\u2009&gt;\u2009A p.Arg502Gln, whereas the other was compound heterozygous for c.1510C\u2009&gt;\u2009T, p.His504Tyr and c.893C\u2009&gt;\u2009A, p.Ser298Ter (NM_014672.4). In vitro tRNA processing assays revealed decreased mitochondrial 5\u2032 tRNA leader cleavage by human RNase P complex with the two novel missense\n                    <jats:italic>PRORP<\/jats:italic>\n                    metallonuclease domain variants. These data provide further evidence that biallelic\n                    <jats:italic>PRORP<\/jats:italic>\n                    variants disrupt 5\u2019 tRNA leader cleavage and are associated with a pleiotropic phenotype of COXPD54.\n                  <\/jats:p>","DOI":"10.1007\/s10048-026-00892-5","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T01:47:32Z","timestamp":1772502452000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the genotypic spectrum of combined oxidative phosphorylation deficiency 54"],"prefix":"10.1007","volume":"27","author":[{"given":"King Lam","family":"Lai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha S.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swetha","family":"Ramadesikan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Koboldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse M.","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Vidaurre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Atanasova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Marsden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wyatt W.","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond T.","family":"O\u2019Keefe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"892_CR1","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1016\/j.ajhg.2021.10.002","volume":"108","author":"I Hochberg","year":"2021","unstructured":"Hochberg I, Demain LAM, Richer J, Thompson K, Urquhart JE, Rea A et al (2021) Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations. Am J Hum Genet 108:2195\u20132204","journal-title":"Am J Hum Genet"},{"issue":"10","key":"892_CR2","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1038\/s41431-023-01437-2","volume":"31","author":"TB Smith","year":"2023","unstructured":"Smith TB, Rea A, Thomas HB, Thompson K, Ol\u00e1hov\u00e1 M, Maroofian R et al (2023) Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54. Eur J Hum Genet 31(10):1190\u20131194","journal-title":"Eur J Hum Genet"},{"key":"892_CR3","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.cell.2008.09.013","volume":"135","author":"J Holzmann","year":"2008","unstructured":"Holzmann J, Frank P, L\u00f6ffler E, Bennett KL, Gerner C, Rossmanith W (2008) RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. Cell 135:462\u2013474","journal-title":"Cell"},{"issue":"1","key":"892_CR4","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s13073-023-01258-4","volume":"15","author":"SJ Lin","year":"2023","unstructured":"Lin SJ, Vona B, Lau T, Huang K, Zaki MS, Aldeen HS, Karimiani EG, Rocca C, Noureldeen MM, Saad AK, Petree C, Bartolomaeus T, Abou Jamra R, Zifarelli G, Gotkhindikar A, Wentzensen IM, Liao M, Cork EE, Varshney P, Hashemi N, Mohammadi MH, Rad A, Neira J, Toosi MB, Knopp C, Kurth I, Challman TD, Smith R, Abdalla A, Haaf T, Suri M, Joshi M, Chung WK, Moreno-De-Luca A, Houlden H, Maroofian R, Varshney GK (2023) Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. Genome Med 15(1):102. https:\/\/doi.org\/10.1186\/s13073-023-01258-4PMID: 38031187; PMCID: PMC10688095","journal-title":"Genome Med"},{"key":"892_CR5","doi-asserted-by":"publisher","first-page":"12885","DOI":"10.1074\/jbc.270.21.12885","volume":"270","author":"W Rossmanith","year":"1995","unstructured":"Rossmanith W, Tullo A, Potuschak T, Karwan R, Sbis E (1995) Human Mitochondrial tRNA Processing. J Biol Chem 270:12885\u201312891","journal-title":"J Biol Chem"},{"key":"892_CR6","doi-asserted-by":"publisher","unstructured":"Alford RF, Leaver-Fay A, Jeliazkov JR, O\u2019Meara MJ, DiMaio FP, Park H, Shapovalov MV, Renfrew PD, Mulligan VK, Kappel K, Labonte JW, Pacella MS, Bonneau R, Bradley P, Dunbrack RL Jr, Das R, Baker D, Kuhlman B, Kortemme T, Gray JJ (2017) The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design. J Chem Theory Comput 13(6):3031\u20133048. https:\/\/doi.org\/10.1021\/acs.jctc.7b00125. Epub 2017 May 12. Erratum in: J Chem Theory Comput. 2022;18(7):4594. doi: 10.1021\/acs.jctc.2c00500. PMID: 28430426; PMCID: PMC5717763","DOI":"10.1021\/acs.jctc.7b00125"},{"key":"892_CR7","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434\u2013443","journal-title":"Nature"},{"key":"892_CR8","doi-asserted-by":"publisher","first-page":"W420","DOI":"10.1093\/nar\/gkac373","volume":"50","author":"Y Xie","year":"2022","unstructured":"Xie Y et al (2022) IBS 2.0: an upgraded illustrator for the visualization of biological sequences. Nucleic acids Res vol 50:W420\u2013W426. https:\/\/doi.org\/10.1093\/nar\/gkac373","journal-title":"Nucleic acids Res vol"},{"issue":"1","key":"892_CR9","doi-asserted-by":"publisher","first-page":"4683","DOI":"10.1038\/s41467-024-49132-0","volume":"15","author":"V Meynier","year":"2024","unstructured":"Meynier V, Hardwick SW, Catala M, Roske JJ, Oerum S, Chirgadze DY, Barraud P, Yue WW, Luisi BF, Tisn\u00e9 C (2024) Structural basis for human mitochondrial tRNA maturation. Nat Commun 15(1):4683. https:\/\/doi.org\/10.1038\/s41467-024-49132-0PMID: 38824131; PMCID: PMC11144196","journal-title":"Nat Commun"},{"key":"892_CR10","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/s41594-021-00637-y","volume":"28","author":"A Bhatta","year":"2021","unstructured":"Bhatta A, Dienemann C, Cramer P, Hillen HS (2021) Structural basis of RNA processing by human mitochondrial RNase P. Nat Struct Mol Biol 28:713\u2013723","journal-title":"Nat Struct Mol Biol"}],"container-title":["Neurogenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10048-026-00892-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10048-026-00892-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10048-026-00892-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:18:59Z","timestamp":1781637539000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10048-026-00892-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":10,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["892"],"URL":"https:\/\/doi.org\/10.1007\/s10048-026-00892-5","relation":{},"ISSN":["1364-6753"],"issn-type":[{"value":"1364-6753","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]},"assertion":[{"value":"18 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20"}}