期刊
BRAIN
卷 143, 期 -, 页码 55-68出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz379
关键词
MN1; MCTT syndrome; craniofacial development; intellectual disability; rhombencephalosynapsis
资金
- Universite Sorbonne Paris-Cite Pole de recherche et d'enseignement superieur [SPC/JFG/2013-031]
- Agence Nationale de la Recherche [CranioRespiro project]
- Agence Nationale de la Recherche ['Investissements d'avenir' program] [ANR-10-IAHU-01]
- MSDAvenir (DevoDecode project)
- Society for the Relief of Disabled Children
- Medix Medical Services Asia
- Nachwuchskommission of the Charite Berlin (Rahel-Hirsch scholarship)
- German Research Foundation (DFG) [SFB1315, LE 4223/1]
- NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54HD083091]
- NIH National Institute of Neurological Diseases and Stroke [R01NS050375]
- NIH National Human Genome Research Institute [HG009599]
- NIH National Human Genome Research Institute
- NIH National Heart, Lung and Blood Institute [UM1 HG006493, U24 HG008956]
- Canadian Institute of Health Research
- BC Children's Hospital Research Institute through its intramural IGAP Clinician Scientist Award program
- Health Innovation Challenge Fund [HICF-1009-003]
- Wellcome
- E-Rare (CRANIRARE project)
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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