{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:30Z","timestamp":1786976850232,"version":"build-2736575974"},"reference-count":22,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM141710"],"award-info":[{"award-number":["R35GM141710"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and cognitive impairments, microcephaly, distinctive facial features, and other features according to the type. Several classes of PCH1 have been linked to mutations in the evolutionarily conserved RNA exosome complex that consists of nine subunits (\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    to\n                    <jats:italic>EXOSC9<\/jats:italic>\n                    ) and facilitates the degradation and processing of cytoplasmic and nuclear RNA from the 3\u2032 end. Only a single individual with an\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    mutation was reported with clinical features of PCH type 1 (PCH1F). Here, we report a 3\u2010month\u2010old female with PCH and additional clinical features not previously reported to be associated with PCH1, including dilated cardiomyopathy. On assessment, failure to thrive, microcephaly, distinctive facial features, and bluish sclera, were noted. Whole\u2010exome sequencing was performed and revealed a novel homozygous missense variant c.547C\u2009&gt;\u2009T (p.Arg183Trp) in the\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    gene. Functional studies in a budding yeast model that expresses the human\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    variant Arg183Trp show a slow\u2010growth phenotype, whereas the previously identified PCH1F allele\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    \u2010Ser35Leu is lethal, indicating impaired exosome function for both of these variants. The protein levels of both\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    variants are reduced compared with wild\u2010type when expressed in budding yeast. Herein, we ascertain the second case of PCH associated with a\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    variant that causes defects in RNA exosome function and provide a model organism system to distinguish between benign and pathogenic variants in\n                    <jats:italic>EXOSC1<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.63198","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T23:34:00Z","timestamp":1680824040000},"page":"1923-1928","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pontocerebellar hypoplasia associated with p.\n                    <scp>Arg183Trp<\/scp>\n                    homozygous variant in\n                    <scp>\n                      <i>EXOSC1<\/i>\n                    <\/scp>\n                    gene: A case report"],"prefix":"10.1002","volume":"191","author":[{"given":"Nadirah S.","family":"Damseh","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Genetics Al Makassed Hospital  East Jerusalem Palestine"},{"name":"Faculty of Medicine Al\u2010Quds University  Abu Deis Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali N.","family":"Obeidat","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Al\u2010Quds University  Abu Deis Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khondakar Sayef","family":"Ahammed","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics University of Texas Health Science Center at Houston  Houston Texas USA"},{"name":"MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motee","family":"Al\u2010Ashhab","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Genetics Al Makassed Hospital  East Jerusalem Palestine"},{"name":"Faculty of Medicine Al\u2010Quds University  Abu Deis Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motee Abu","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Genetics Al Makassed Hospital  East Jerusalem Palestine"},{"name":"Faculty of Medicine Al\u2010Quds University  Abu Deis Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambro","family":"van Hoof","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics University of Texas Health Science Center at Houston  Houston Texas USA"},{"name":"MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.16.2148"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","unstructured":"Appelhof B. 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