{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T03:05:42Z","timestamp":1761102342341,"version":"3.37.3"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T00:00:00Z","timestamp":1536105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Beta\u2010galactosidase\u20101 <jats:bold>(<\/jats:bold><jats:styled-content style=\"fixed-case\">GLB<\/jats:styled-content>1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly <jats:styled-content style=\"fixed-case\">GM<\/jats:styled-content>1 (monosialotetrahexosylganglioside). Pathogenic variants in <jats:italic><jats:styled-content style=\"fixed-case\">GLB<\/jats:styled-content>1<\/jats:italic> cause two different lysosomal storage disorders: <jats:styled-content style=\"fixed-case\">GM<\/jats:styled-content>1 gangliosidosis and mucopolysaccharidosis type <jats:styled-content style=\"fixed-case\">IVB<\/jats:styled-content>. In <jats:styled-content style=\"fixed-case\">GM<\/jats:styled-content>1 gangliosidosis, decreased \u03b2\u2010galactosidase\u20101 enzymatic activity leads to the accumulation of <jats:styled-content style=\"fixed-case\">GM<\/jats:styled-content>1 gangliosides, predominantly within the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>. We present a 22\u2010month\u2010old proband with <jats:styled-content style=\"fixed-case\">GM<\/jats:styled-content>1 gangliosidosis type <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> (late\u2010infantile form) in whom a novel homozygous in\u2010frame deletion (c.1468_1470del<jats:styled-content style=\"fixed-case\">AAC<\/jats:styled-content>, p.Asn490del) in <jats:italic><jats:styled-content style=\"fixed-case\">GLB<\/jats:styled-content>1<\/jats:italic> was detected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used an experimental protein structure of \u03b2\u2010galactosidase\u20101 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild\u2010type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Molecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of \u03b2\u2010galactosidase\u20101 substrates. Enzyme assays confirmed diminished <jats:styled-content style=\"fixed-case\">GLB<\/jats:styled-content>1 enzymatic activity (~3% of normal activity) in the proband.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We have described a novel, pathogenic in\u2010frame deletion of <jats:italic><jats:styled-content style=\"fixed-case\">GLB<\/jats:styled-content>1<\/jats:italic> in a patient with <jats:styled-content style=\"fixed-case\">GM<\/jats:styled-content>1 gangliosidosis type <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.454","type":"journal-article","created":{"date-parts":[[2018,9,6]],"date-time":"2018-09-06T04:11:27Z","timestamp":1536207087000},"page":"1229-1235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Protein modeling and clinical description of a novel in\u2010frame <i><scp>GLB<\/scp>1<\/i> deletion causing <scp>GM<\/scp>1 gangliosidosis type <scp>II<\/scp>"],"prefix":"10.1002","volume":"6","author":[{"suffix":"Jr.","given":"John E.","family":"Richter","sequence":"first","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic Jacksonville Florida"},{"name":"Center for Individualized Medicine Mayo Clinic Jacksonville Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael T.","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0658-1275","authenticated-orcid":false,"given":"Patrick R.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester Minnesota"},{"name":"Center for Individualized Medicine Mayo Clinic Rochester Minnesota"},{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed N.","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic Jacksonville Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric W.","family":"Klee","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic Jacksonville Florida"},{"name":"Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester Minnesota"},{"name":"Center for Individualized Medicine Mayo Clinic Rochester Minnesota"},{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura M.","family":"Pollard","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Laboratory Greenwood Genetic Center Greenwood South Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colleen F.","family":"Macmurdo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Baylor Scott &amp; White Health Temple Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8515-744X","authenticated-orcid":false,"given":"Paldeep S.","family":"Atwal","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic Jacksonville Florida"},{"name":"Center for Individualized Medicine Mayo Clinic Jacksonville Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1055-3069","authenticated-orcid":false,"given":"Thomas R.","family":"Caulfield","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic Jacksonville Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,9,5]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_9_2_1","DOI":"10.1016\/j.ymgme.2008.04.012"},{"doi-asserted-by":"publisher","key":"e_1_2_9_3_1","DOI":"10.1016\/j.bbadis.2011.03.018"},{"doi-asserted-by":"publisher","key":"e_1_2_9_4_1","DOI":"10.1371\/journal.pcbi.1003935"},{"doi-asserted-by":"publisher","key":"e_1_2_9_5_1","DOI":"10.1016\/j.jsb.2011.07.015"},{"doi-asserted-by":"publisher","key":"e_1_2_9_6_1","DOI":"10.1002\/jcc.20387"},{"doi-asserted-by":"publisher","key":"e_1_2_9_7_1","DOI":"10.1016\/j.annepidem.2012.02.006"},{"doi-asserted-by":"publisher","key":"e_1_2_9_8_1","DOI":"10.1038\/mt.2014.68"},{"doi-asserted-by":"publisher","key":"e_1_2_9_9_1","DOI":"10.1007\/s11011-017-0044-y"},{"unstructured":"D.S.M.E. 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