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

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.

Assessing the impact of the U.S. Endangered Species Act recovery planning guidelines on managing threats for listed species.

The Endangered Species Act (ESA) of the United States was enacted in 1973 to prevent the extinction of species. Recovery plans, required by 1988 amendments to the ESA, play an important role in organizing these efforts to protect and recover species. To improve the use of science in the recovery planning process, the Society for Conservation Biology (SCB) commissioned an independent review of endangered species recovery planning in 1999. From these findings, the SCB made key recommendations for how management agencies could improve the recovery planning process, after which the U.S. Fish and Wildlife Service and the National Marine Fisheries Service redrafted their recovery planning guidelines. One important recommendation called for recovery plans to make threats a primary focus, including organizing and prioritizing recovery tasks for threat abatement. We sought to determine the extent to which results from the SCB study were incorporated into these new guidelines and whether the SCB recommendations regarding threats manifested in recovery plans written under the new guidelines. Recovery planning guidelines generally incorporated the SCB recommendations, including those for managing threats. However, although recent recovery plans have improved in their treatment of threats, many fail to adequately incorporate threat monitoring. This failure suggests that developing clear guidelines for monitoring should be an important priority in improving ESA recovery planning.