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

Brain. 2020 Jan 1;143(1):55-68. doi: 10.1093/brain/awz379.

Abstract

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.

Keywords: MCTT syndrome; MN1; craniofacial development; intellectual disability; rhombencephalosynapsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Basilar Artery / abnormalities
  • Basilar Artery / diagnostic imaging
  • Carotid Arteries / abnormalities
  • Carotid Arteries / diagnostic imaging
  • Cerebellar Vermis / abnormalities
  • Cerebellar Vermis / diagnostic imaging
  • Cerebellum / abnormalities
  • Cerebellum / diagnostic imaging
  • Child
  • Child, Preschool
  • Cohort Studies
  • Comparative Genomic Hybridization
  • Craniofacial Abnormalities / diagnostic imaging
  • Craniofacial Abnormalities / genetics*
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Imaging, Three-Dimensional
  • Infant
  • Intellectual Disability / genetics*
  • Language Development Disorders / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation
  • Nervous System Malformations / diagnostic imaging
  • Nervous System Malformations / genetics*
  • Nonsense Mediated mRNA Decay
  • Polymicrogyria / diagnostic imaging
  • Polymicrogyria / genetics
  • RNA-Seq
  • Real-Time Polymerase Chain Reaction
  • Syndrome
  • Tomography, X-Ray Computed
  • Trans-Activators / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Whole Exome Sequencing
  • Whole Genome Sequencing

Substances

  • MN1 protein, human
  • Trans-Activators
  • Tumor Suppressor Proteins