Wednesday, October 19, 2022

MN1 C-terminal truncation syndrome

Inspired by a patient

Yu J, Li C, Chen J, Ran Q, Zhao Y, Cao Q, Chen X, Yu L, Li W, Zhao Z. Diagnosis and treatment of MN1 C-terminal truncation syndrome. Mol Genet Genomic Med. 2022 Sep 20:e1965. doi: 10.1002/mgg3.1965. Epub ahead of print. PMID: 36124717.


Background: MN1 C-terminal truncation (MCTT) is a rare syndrome; only 27 cases have been reported. We report the first case of an 8-year-old girl with MCTT syndrome complicated with moderate obstructive sleep apnea (OSA).

Methods: MCTT syndrome was diagnosed by whole-exome sequencing (WES) and validated by Sanger sequencing. The patient received 2 years of treatment with continuous positive airway pressure (CPAP) to relieve sleep apnea and hypoxia, and a reverse sector fan-shaped expander for maxillary expansion.

Results: WES revealed a de novo MN1 variant, c.3760C>T (p.[Q1254*]). An arachnoid cyst was found in the right occipital brain. The patient presented mild symptoms of classic MCTT syndrome. The patient did not experience hearing loss and only mild intellectual disability. Radiological examinations showed cleft secondary palate, narrow upper arch, narrow upper airway, and mandibular skeletal retrusion. Polysomnography indicated moderate OSA, with an apnea/hypopnea index of 6.8, which decreased to 1 after CPAP during the night. Two-year maxillary expansion widened the upper arch, and the cleft secondary palate became visible. The mandible moved forward spontaneously, resulting in the improvement of profile and upper airway widening. General physical conditions, such as motor delay, muscle weakness, and developmental delay, were significantly improved two years later.

Conclusion: In conclusion, we discovered a MN1 variant [NM_002430.2: c.3760C>T, p.Q1254*] that causes mild MCTT symptoms compared to other MN1 variants. For patients with MCTT complicated with OSA, multidisciplinary combination therapy can improve maxillofacial development, widen the upper airway and relieve sleep apnea, improving the general physical condition.

Mak CCY, Doherty D, Lin AE, Vegas N, Cho MT, Viot G, Dimartino C, Weisfeld-Adams JD, Lessel D, Joss S, Li C, Gonzaga-Jauregui C, Zarate YA, Ehmke N, Horn D, Troyer C, Kant SG, Lee Y, Ishak GE, Leung G, Barone Pritchard A, Yang S, Bend EG, Filippini F, Roadhouse C, Lebrun N, Mehaffey MG, Martin PM, Apple B, Millan F, Puk O, Hoffer MJV, Henderson LB, McGowan R, Wentzensen IM, Pei S, Zahir FR, Yu M, Gibson WT, Seman A, Steeves M, Murrell JR, Luettgen S, Francisco E, Strom TM, Amlie-Wolf L, Kaindl AM, Wilson WG, Halbach S, Basel-Salmon L, Lev-El N, Denecke J, Vissers LELM, Radtke K, Chelly J, Zackai E, Friedman JM, Bamshad MJ, Nickerson DA; University of Washington Center for Mendelian Genomics, Reid RR, Devriendt K, Chae JH, Stolerman E, McDougall C, Powis Z, Bienvenu T, Tan TY, Orenstein N, Dobyns WB, Shieh JT, Choi M, Waggoner D, Gripp KW, Parker MJ, Stoler J, Lyonnet S, Cormier-Daire V, Viskochil D, Hoffman TL, Amiel J, Chung BHY, Gordon CT. 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. Erratum in: Brain. 2020 Mar 1;143(3):e24. PMID: 31834374; PMCID: PMC7962909.


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.

Miyake N, Takahashi H, Nakamura K, Isidor B, Hiraki Y, Koshimizu E, Shiina M, Sasaki K, Suzuki H, Abe R, Kimura Y, Akiyama T, Tomizawa SI, Hirose T, Hamanaka K, Miyatake S, Mitsuhashi S, Mizuguchi T, Takata A, Obo K, Kato M, Ogata K, Matsumoto N. Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities. Am J Hum Genet. 2020 Jan 2;106(1):13-25. doi: 10.1016/j.ajhg.2019.11.011. Epub 2019 Dec 12. PMID: 31839203; PMCID: PMC7042485.


MN1 was originally identified as a tumor-suppressor gene. Knockout mouse studies have suggested that Mn1 is associated with craniofacial development. However, no MN1-related phenotypes have been established in humans. Here, we report on three individuals who have de novo MN1 variants that lead to a protein lacking the carboxyl (C) terminus and who presented with severe developmental delay, craniofacial abnormalities with specific facial features, and structural abnormalities in the brain. An in vitro study revealed that the deletion of the C-terminal region led to increased protein stability, an inhibitory effect on cell proliferation, and enhanced MN1 aggregation in nuclei compared to what occurred in the wild type, suggesting that a gain-of-function mechanism is involved in this disease. Considering that C-terminal deletion increases the fraction of intrinsically disordered regions of MN1, it is possible that altered phase separation could be involved in the mechanism underlying the disease. Our data indicate that MN1 participates in transcriptional regulation of target genes through interaction with the transcription factors PBX1, PKNOX1, and ZBTB24 and that mutant MN1 impairs the binding with ZBTB24 and RING1, which is an E3 ubiquitin ligase. On the basis of our findings, we propose the model that C-terminal deletion interferes with MN1's interaction molecules related to the ubiquitin-mediated proteasome pathway, including RING1, and increases the amount of the mutant protein; this increase leads to the dysregulation of MN1 target genes by inhibiting rapid MN1 protein turnover.

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