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Article: MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis

TitleMN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis
Authors
KeywordsMCTT syndrome
MN1
craniofacial development
intellectual disability
rhombencephalosynapsis
Issue Date2020
PublisherOxford University Press. The Journal's web site is located at http://brain.oxfordjournals.org/
Citation
Brain, 2020, v. 143 n. 1, p. 55-68 How to Cite?
AbstractMN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental 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 8/10 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 exon 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-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
Persistent Identifierhttp://hdl.handle.net/10722/281231
ISSN
2017 Impact Factor: 10.848
2015 SCImago Journal Rankings: 6.097

 

DC FieldValueLanguage
dc.contributor.authorMak, CCY-
dc.contributor.authorDoherty, D-
dc.contributor.authorLin, AE-
dc.contributor.authorVegas, N-
dc.contributor.authorCho, MT-
dc.contributor.authorViot, G-
dc.contributor.authorDimartino, C-
dc.contributor.authorWeisfeld-Adams, JD-
dc.contributor.authorLessel, D-
dc.contributor.authorJoss, S-
dc.contributor.authorLi, C-
dc.contributor.authorGonzaga-Jauregui, C-
dc.contributor.authorZarate, YA-
dc.contributor.authorEhmke, N-
dc.contributor.authorHorn, D-
dc.contributor.authorTroyer, C-
dc.contributor.authorKant, SG-
dc.contributor.authorLee, Y-
dc.contributor.authorIshak, GE-
dc.contributor.authorLeung, G-
dc.contributor.authorBarone Pritchard, A-
dc.contributor.authorYang, S-
dc.contributor.authorBend, EG-
dc.contributor.authorFilippini, F-
dc.contributor.authorRoadhouse, C-
dc.contributor.authorLebrun, N-
dc.contributor.authorMehaffey, MG-
dc.contributor.authorMartin, P-M-
dc.contributor.authorApple, B-
dc.contributor.authorMillan, F-
dc.contributor.authorPuk, O-
dc.contributor.authorHoffer, MJV-
dc.contributor.authorHenderson, LB-
dc.contributor.authorMcGowan, R-
dc.contributor.authorWentzensen, IM-
dc.contributor.authorPei, S-
dc.contributor.authorZahir, FR-
dc.contributor.authorYU, M-
dc.contributor.authorGibson, WT-
dc.contributor.authorSenab, A-
dc.contributor.authorSteeves, M-
dc.contributor.authorMurrell, JR-
dc.contributor.authorLuettgen, S-
dc.contributor.authorFrancisco, E-
dc.contributor.authorStrom, TM-
dc.contributor.authorAmlie-Wolf, L-
dc.contributor.authorKaindl, AM-
dc.contributor.authorWilson, WG-
dc.contributor.authorHalbach, S-
dc.contributor.authorBasel-Salmon, L-
dc.contributor.authorLev-El, N-
dc.contributor.authorDenecke, J-
dc.contributor.authorVissers, LELM-
dc.contributor.authorRadtke, K-
dc.contributor.authorChelly, J-
dc.contributor.authorZackai, E-
dc.contributor.authorFriedman, JM-
dc.contributor.authorBamshad, MJ-
dc.contributor.authorNickerson, DA-
dc.contributor.authorReid, RR-
dc.contributor.authorDevriendt, K-
dc.contributor.authorChae, JH-
dc.contributor.authorStolerman, E-
dc.contributor.authorMcDougall, C-
dc.contributor.authorPowis, Z-
dc.contributor.authorBienvenu, T-
dc.contributor.authorTan, TY-
dc.contributor.authorOrenstein, N-
dc.contributor.authorDobyns, WB-
dc.contributor.authorShieh, JT-
dc.contributor.authorChoi, M-
dc.contributor.authorWaggoner, D-
dc.contributor.authorGripp, KW-
dc.contributor.authorParker, MJ-
dc.contributor.authorStoler, J-
dc.contributor.authorLyonnet, S-
dc.contributor.authorCormier-Daire, V-
dc.contributor.authorViskochil, D-
dc.contributor.authorHoffman, TL-
dc.contributor.authorAmiel, J-
dc.contributor.authorChung, BHY-
dc.contributor.authorGordon, CT-
dc.contributor.authorUniversity of Washington Center for Mendelian Genomics-
dc.date.accessioned2020-03-09T09:51:54Z-
dc.date.available2020-03-09T09:51:54Z-
dc.date.issued2020-
dc.identifier.citationBrain, 2020, v. 143 n. 1, p. 55-68-
dc.identifier.issn0006-8950-
dc.identifier.urihttp://hdl.handle.net/10722/281231-
dc.description.abstractMN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental 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 8/10 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 exon 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-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://brain.oxfordjournals.org/-
dc.relation.ispartofBrain-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here].-
dc.subjectMCTT syndrome-
dc.subjectMN1-
dc.subjectcraniofacial development-
dc.subjectintellectual disability-
dc.subjectrhombencephalosynapsis-
dc.titleMN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis-
dc.typeArticle-
dc.identifier.emailMak, CCY: ccymak@connect.hku.hk-
dc.identifier.emailTan, TY: tanty@hku.hk-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityTan, TY=rp01380-
dc.identifier.authorityChung, BHY=rp00473-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/brain/awz379-
dc.identifier.pmid31834374-
dc.identifier.scopuseid_2-s2.0-85077349592-
dc.identifier.hkuros309268-
dc.identifier.volume143-
dc.identifier.issue1-
dc.identifier.spage55-
dc.identifier.epage68-
dc.publisher.placeUnited Kingdom-

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