{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:51:55Z","timestamp":1790175115409,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,12,17]],"date-time":"2018-12-17T00:00:00Z","timestamp":1545004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:p>Autosomal recessive<jats:italic>PRUNE1<\/jats:italic>mutations are reported to cause a severe neurodevelopmental disorder with microcephaly, hypotonia, and brain malformations. We describe clinical and neuropathological features in a cohort of nine individuals of Cree descent who, because of a founder effect, are homozygous for the same<jats:italic>PRUNE1<\/jats:italic>mutation. They follow the course of a combined neuromuscular and neurodegenerative disease, rather than a pure failure of normal development. This cohort presented in infancy with features of lower motor neuron disease, such as hypotonia, contractures, tongue fasciculations, and feeding difficulties in the absence of congenital brain anomalies and microcephaly. A neurodegenerative course followed with onset of seizures, spasticity, and respiratory insufficiency. Muscle biopsies showed denervation\/reinnervation features, nonspecific atrophy and end\u2010stage atrophy. Autopsy findings in two patients are also described, suggesting length dependent central motor axon degeneration, peripheral motor axon degeneration, possible spinal motor neuron degeneration, and accumulation of beta amyloid precursor protein inclusions in select brainstem nuclei. Exome sequencing and homozygosity mapping identified a homozygous<jats:italic>PRUNE1<\/jats:italic>mutation in a canonical splice site, which produces two abnormal<jats:italic>PRUNE1<\/jats:italic>mRNA products. Based on our studies and the histopathology and phenotypic data, we provide further evidence that this disorder leads to a neurodegenerative disease affecting both the peripheral and central nervous systems and suggest that the pathogenic c.521\u20102A&gt;G mutation could lead to an altered effect on tubulin dynamics.<\/jats:p>","DOI":"10.1002\/ajmg.a.60690","type":"journal-article","created":{"date-parts":[[2018,12,17]],"date-time":"2018-12-17T08:15:57Z","timestamp":1545034557000},"page":"206-218","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A homozygous canonical splice acceptor site mutation in PRUNE1 is responsible for a rare childhood neurodegenerative disease in Manitoba Cree families"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4221-8820","authenticated-orcid":false,"given":"Jessica N.","family":"Hartley","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0391-8821","authenticated-orcid":false,"given":"Louise R.","family":"Simard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Ly","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8366-0394","authenticated-orcid":false,"given":"Marc R.","family":"Del Bigio","sequence":"additional","affiliation":[{"name":"Department of Pathology, Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9673-795X","authenticated-orcid":false,"given":"Patrick","family":"Frosk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada"},{"name":"Department of Pediatrics and Child Health, Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/2329048X17752237"},{"key":"e_1_2_8_3_1","article-title":"PRUNE1 deficiency: Expanding the clinical and genetic Spectrum","author":"Alhaddad B.","year":"2018","journal-title":"Neuropediatrics"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-006-9044-z"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38066"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182267bd8"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp215"},{"issue":"21","key":"e_1_2_8_8_1","first-page":"4635","article-title":"Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway","volume":"25","author":"Edvardson S.","year":"2016","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2013-101715"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.035600"},{"issue":"2","key":"e_1_2_8_11_1","first-page":"123","article-title":"Increased prevalence of hereditary metabolic diseases among native Indians in Manitoba and northwestern Ontario","volume":"145","author":"Haworth J. 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