MN1 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.
Bibliographical noteFunding Information:
This work was supported by grants from the Université Sorbonne Paris-Cité Pôle de recherche et d’enseignement supérieur (project number SPC/JFG/2013-031), the Agence Nationale de la Recherche [CranioRespiro project and ‘Investissements d’avenir’ program (ANR-10-IAHU-01)], MSDAvenir (DevoDecode project), E-Rare (CRANIRARE project), The Society for the Relief of Disabled Children, Medix Medical Services Asia, the Nachwuchskommission of the Charité Berlin (Rahel-Hirsch scholarship) to N.E., the German Research Foundation (DFG; SFB1315 to A.M.K. and LE 4223/1 to D.L.), the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083091, Genetics Core) to D.D., the NIH National Institute of Neurological Diseases and Stroke (R01NS050375) to W.B.D., the NIH National Human Genome Research Institute (HG009599) to J.T.S., the NIH National Human Genome Research Institute and the NIH National Heart, Lung and Blood Institute (grants UM1 HG006493 and U24 HG008956) to M.J.B. and D.A.N. (for sequencing provided by the University of Washington Center for Mendelian Genomics) and by private donations from families to D.D. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. F.R.Z. was supported by a Canadian Institute of Health Research fellowship and W.T.G. was supported by the BC Children’s Hospital Research Institute through its intramural IGAP Clinician Scientist Award program. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome. See Deciphering Developmental Disorders Study (2015) or www.ddduk.org/access.html for full acknowledgement.
- MCTT syndrome
- craniofacial development
- intellectual disability
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't