{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:17:17Z","timestamp":1778656637244,"version":"3.51.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100004856","name":"New York State Department of Health","doi-asserted-by":"publisher","award":["C30293GG"],"award-info":[{"award-number":["C30293GG"]}],"id":[{"id":"10.13039\/100004856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012636","name":"New York State Stem Cell Science","doi-asserted-by":"publisher","award":["CO29155"],"award-info":[{"award-number":["CO29155"]}],"id":[{"id":"10.13039\/100012636","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HD082568"],"award-info":[{"award-number":["HD082568"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Approximately 7% of men worldwide suffer from infertility, with sperm abnormalities being the most common defect. Though genetic causes are thought to underlie a substantial fraction of idiopathic cases, the actual molecular bases are usually undetermined. Because the consequences of most genetic variants in populations are unknown, this complicates genetic diagnosis even after genome sequencing of patients. Some patients with ciliopathies, including primary ciliary dyskinesia and Bardet\u2013Biedl syndrome, also suffer from infertility because cilia and sperm flagella share several characteristics. Here, we identified two deleterious alleles of RABL2A, a gene essential for normal function of cilia and flagella. Our in silico predictions and in vitro assays suggest that both alleles destabilize the protein. We constructed and analyzed mice homozygous for these two single-nucleotide polymorphisms, Rabl2L119F (rs80006029) and Rabl2V158F (rs200121688), and found that they exhibit ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus. Our study provides a paradigm for triaging candidate infertility variants in the population for in vivo functional validation, using computational, in vitro and in vivo approaches.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa230","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T15:22:54Z","timestamp":1602602574000},"page":"3402-3411","source":"Crossref","is-referenced-by-count":17,"title":["Variants in\n                    <i>RABL2A<\/i>\n                    causing male infertility and ciliopathy"],"prefix":"10.1093","volume":"29","author":[{"given":"Xinbao","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Fragoza","sequence":"additional","affiliation":[{"name":"Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA"},{"name":"Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priti","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA"},{"name":"Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-1876","authenticated-orcid":false,"given":"John C","family":"Schimenti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"2020121910194148000_ref1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12958-015-0032-1","article-title":"A unique view on male infertility around the globe","volume":"13","author":"Agarwal","year":"2015","journal-title":"Reprod. Biol. Endocrinol."},{"key":"2020121910194148000_ref2","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1007\/s00467-010-1731-7","article-title":"Ciliopathies: an expanding disease spectrum","volume":"26","author":"Waters","year":"2011","journal-title":"Pediatr. Nephrol."},{"key":"2020121910194148000_ref3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1002969","article-title":"RAB-like 2 has an essential role in male fertility, sperm intra-flagellar transport, and tail assembly","volume":"8","author":"Lo","year":"2012","journal-title":"PLoS Genet."},{"key":"2020121910194148000_ref4","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.devcel.2017.05.016","article-title":"The CEP19-RABL2 GTPase complex binds IFT-B to initiate intraflagellar transport at the ciliary base","volume":"42","author":"Kanie","year":"2017","journal-title":"Dev. 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Steril."},{"key":"2020121910194148000_ref8","doi-asserted-by":"crossref","first-page":"D874","DOI":"10.1093\/nar\/gky821","article-title":"AWESOME: a database of SNPs that affect protein post-translational modifications","volume":"47","author":"Yang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2020121910194148000_ref9","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"2020121910194148000_ref10","doi-asserted-by":"crossref","first-page":"10431","DOI":"10.1073\/pnas.1506974112","article-title":"The genetics of human infertility by functional interrogation of SNPs in mice","volume":"112","author":"Singh","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2020121910194148000_ref11","first-page":"3911","article-title":"A putative human infertility allele of the meiotic recombinase DMC1 does not affect fertility in mice","volume":"27","author":"Tran","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"2020121910194148000_ref12","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/biolre\/ioz089","article-title":"A segregating human allele of SPO11 modeled in mice disrupts timing and amounts of meiotic recombination, causing oligospermia and a decreased ovarian reserve\u2020","volume":"101","author":"Tran","year":"2019","journal-title":"Biol. Reprod."},{"key":"2020121910194148000_ref13","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1093\/molehr\/gaz048","article-title":"A predicted deleterious allele of the essential meiosis gene MND1, present in ~3% of East Asians, does not disrupt reproduction in mice","volume":"10","author":"Tran","year":"2019","journal-title":"Mol. Hum. Reprod."},{"key":"2020121910194148000_ref14","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"2020121910194148000_ref15","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc."},{"key":"2020121910194148000_ref16","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. 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A."},{"key":"2020121910194148000_ref18","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1006\/geno.1999.5889","article-title":"Two novel human RAB genes with near identical sequence each map to a telomere-associated region: the subtelomeric region of 22q13.3 and the ancestral telomere band 2q13","volume":"59","author":"Wong","year":"1999","journal-title":"Genomics"},{"key":"2020121910194148000_ref19","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1093\/hmg\/11.6.715","article-title":"Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus","volume":"11","author":"Iba\u00f1ez-Tallon","year":"2002","journal-title":"Hum. Mol. 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Rep."},{"key":"2020121910194148000_ref31","doi-asserted-by":"crossref","first-page":"W306","DOI":"10.1093\/nar\/gki375","article-title":"I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure","volume":"33","author":"Capriotti","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2020121910194148000_ref32","doi-asserted-by":"crossref","first-page":"W350","DOI":"10.1093\/nar\/gky300","article-title":"DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability","volume":"46","author":"Rodrigues","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2020121910194148000_ref33","doi-asserted-by":"crossref","first-page":"W229","DOI":"10.1093\/nar\/gkx439","article-title":"SDM: a server for predicting effects of mutations on protein stability","volume":"45","author":"Pandurangan","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2020121910194148000_ref34","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1021\/acs.jcim.8b00697","article-title":"Deepddg: predicting the stability change of protein point mutations using neural networks","volume":"59","author":"Cao","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"2020121910194148000_ref35","doi-asserted-by":"crossref","first-page":"W314","DOI":"10.1093\/nar\/gku411","article-title":"DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach","volume":"42","author":"Pires","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2020121910194148000_ref36","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/bioinformatics\/btt691","article-title":"mCSM: predicting the effects of mutations in proteins using graph-based signatures","volume":"30","author":"Pires","year":"2014","journal-title":"Bioinformatics"},{"key":"2020121910194148000_ref37","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1038\/s41467-019-11959-3","article-title":"Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations","volume":"10","author":"Fragoza","year":"2019","journal-title":"Nat. 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