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dc.contributor.authorCoolen, M
dc.contributor.authorAltin, N
dc.contributor.authorRajamani, K
dc.contributor.authorPereira, E
dc.contributor.authorSiquier-Pernet, K
dc.contributor.authorPuig Lombardi, E
dc.contributor.authorMoreno, N
dc.contributor.authorBarcia, G
dc.contributor.authorYvert, M
dc.contributor.authorLaquerrière, A
dc.contributor.authorPouliet, A
dc.contributor.authorNitschké, P
dc.contributor.authorBoddaert, N
dc.contributor.authorRausell, A
dc.contributor.authorRazavi, F
dc.contributor.authorAfenjar, A
dc.contributor.authorBillette de Villemeur, T
dc.contributor.authorAl-Maawali, A
dc.contributor.authorAl-Thihli, K
dc.contributor.authorBaptista, J
dc.contributor.authorBeleza-Meireles, A
dc.contributor.authorGarel, C
dc.contributor.authorLegendre, M
dc.contributor.authorGelot, A
dc.contributor.authorBurglen, L
dc.contributor.authorMoutton, S
dc.contributor.authorCantagrel, V
dc.date.accessioned2022-05-03T17:23:46Z
dc.date.issued2022-05-05
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.urihttp://hdl.handle.net/10026.1/19158
dc.description.abstract

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

dc.format.extent909-927
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoeng
dc.publisherCell Press
dc.subjectPRDM13
dc.subjectPurkinje cells
dc.subjectbrainstem
dc.subjectcerebellum
dc.subjectinferior olive nuclei
dc.subjectneurodevelopment
dc.subjectneuronal specification
dc.subjectolivopontocerebellar hypoplasia
dc.subjectzebrafish
dc.subjectAnimals
dc.subjectBrain Diseases
dc.subjectBrain Stem
dc.subjectCerebellum
dc.subjectDevelopmental Disabilities
dc.subjectHistone-Lysine N-Methyltransferase
dc.subjectHumans
dc.subjectMice
dc.subjectMutation
dc.subjectNervous System Malformations
dc.subjectNeurogenesis
dc.subjectPurkinje Cells
dc.subjectTranscription Factors
dc.subjectZebrafish
dc.titleRecessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cells differentiation
dc.typejournal-article
dc.typeArticle
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/35390279
plymouth.issue5
plymouth.volume109
plymouth.publisher-urlhttp://dx.doi.org/10.1016/j.ajhg.2022.03.010
plymouth.publication-statusPublished
plymouth.journalAmerican Journal of Human Genetics
dc.identifier.doi10.1016/j.ajhg.2022.03.010
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeUnited States
dcterms.dateAccepted2022-03-11
dc.rights.embargodate2022-11-5
dc.identifier.eissn1537-6605
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1016/j.ajhg.2022.03.010
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2022-04-04
rioxxterms.typeJournal Article/Review


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