{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:45:00Z","timestamp":1789055100448,"version":"build-2803163510"},"reference-count":22,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Int Med Res"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Split-hand\/foot malformation (SHFM) is a rare, often debilitating, congenital limb malformation. A single nucleotide polymorphism within the leucine zipper containing kinase AZK ( ZAK) gene was recently associated with SHFM in two consanguineous Pakistani pedigrees. We hypothesized that additional unrelated patients with the phenotype may carry a pathogenic mutation in ZAK.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>DNA samples were collected from 38 patients with SHFM and associated hearing loss for Sanger DNA sequencing and in silico analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Two missense mutations within ZAK were detected in 11 patients, but only one missense variant, p.Ala505Ser, occurred with a presumed rare allele frequency. In silico modeling of the ZAK protein with the p.Ala505Ser substitution indicated a negative binding free energy change (mean \u0394\u0394G\u2009=\u2009\u22120.9), representing destabilization of the ZAK tertiary structure. Additional laboratory analysis demonstrated a chromosome region 7q21.3-q22.1 deletion. This locus contains the SHFM-1 causative genes SHFM1, DLX5, and DLX6 (distal-less homeobox-5 and -6).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We report a novel and rare missense variant, ZAK p.Ala505Ser, in one patient with SHFM from a non-consanguineous pedigree. This variant mildly destabilizes the ZAK tertiary structure. Although this mutation involved a deletion at the SHFM1 locus (7q21.3-q22.1), ZAK signaling destabilization may have contributed to the phenotype, which included hearing loss.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/0300060519879293","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T08:16:22Z","timestamp":1586333782000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand\/foot malformation from a non-consanguineous pedigree"],"prefix":"10.1177","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4113-5038","authenticated-orcid":false,"given":"Christopher Ronald","family":"Funk","sequence":"first","affiliation":[{"name":"J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, SC, United States"},{"name":"Emory University School of Medicine, Atlanta, GA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth S.","family":"Huey","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville, SC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie M.","family":"May","sequence":"additional","affiliation":[{"name":"J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, SC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhui","family":"Peng","sequence":"additional","affiliation":[{"name":"Computational Biophysics and Bioinformatics Laboratory, Department of Physics and Astronomy, Clemson University, Clemson, SC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Michonova","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Physics, Erskine College, Due West, SC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Best","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville, SC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, SC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna V.","family":"Blenda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville, SC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,4,8]]},"reference":[{"key":"bibr1-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36239"},{"key":"bibr2-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1242\/dev.011759"},{"key":"bibr3-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1995.9981"},{"key":"bibr4-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1086\/302972"},{"key":"bibr5-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1086\/302467"},{"key":"bibr6-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn164"},{"key":"bibr7-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1101\/gr.199430.115"},{"key":"bibr8-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13434"},{"key":"bibr9-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.133"},{"key":"bibr10-0300060519879293","first-page":"17","author":"Funk CR","year":"2017","journal-title":"J Undergrad Res Sch Excell"},{"key":"bibr11-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.053"},{"key":"bibr12-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw306"},{"key":"bibr13-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt691"},{"key":"bibr14-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr363"},{"key":"bibr15-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku411"},{"key":"bibr16-0300060519879293","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17040512"},{"key":"bibr17-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki375"},{"key":"bibr18-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100556"},{"key":"bibr19-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2001.590105.x"},{"key":"bibr20-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31244"},{"key":"bibr21-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1101\/gad.988402"},{"key":"bibr22-0300060519879293","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv514"}],"container-title":["Journal of International Medical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0300060519879293","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/0300060519879293","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0300060519879293","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:45:21Z","timestamp":1777459521000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/0300060519879293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4]]},"references-count":22,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1177\/0300060519879293"],"URL":"https:\/\/doi.org\/10.1177\/0300060519879293","relation":{},"ISSN":["0300-0605","1473-2300"],"issn-type":[{"value":"0300-0605","type":"print"},{"value":"1473-2300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4]]},"article-number":"0300060519879293"}}