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MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.
Brain 143, 55-68 (2020)
Verlagsversion Forschungsdaten DOI
MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions cricoinp:wiing, MN1 have here reported in individuals with variable neurodevclop-mental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/21 individuals. rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery, MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of eNon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. we propose that the condition described here, MN1 C-termirim truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominandy acting C-terminally MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door t understanding the biological mechanisms underlying rhombencephalosynapsis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mn1 ; Mctt Syndrome ; Craniofacial Development ; Intellectual Disability ; Rhombencephalosynapsis; Cause Intellectual Disability; Acute Myeloid-leukemia; De-novo Mutations; Transcription Factor; Translocation; Protein; Overexpression; Imbalance; Spectrum; Deletion
ISSN (print) / ISBN 0006-8950
Zeitschrift Brain: A Journal of Neurology
Quellenangaben Band: 143, Heft: 1, Seiten: 55-68
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)