Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate

Breckpot, Jeroen; Anderlid, Britt‐Marie; Alanay, Yasemin; Blyth, Moira; Brahimi, Afane; Duban‐Bedu, Bénédicte; Gozé, Odile; Firth, Helen V.; Yakıcıer, Mustafa Cengiz; Hens, Greet; Rayyan, Maissa; Legius, Eric; Vermeesch, Joris Robert; Devriendt, Koen

doi:10.1038/ejhg.2015.65

Cited by 10 publications

(7 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Breckpot et al. ). The candidate gene in this location that is associated with palate development is the transcription factor MN1.…”

Section: Discussionmentioning

confidence: 98%

“…In addition to the aforementioned syndromes, several deletions affecting chromosome 22 lead to soft palate clefts. Microdeletions of chromosome 22q12 cause cleft soft palate (Davidson et al 2012;Beck et al 2015;Breckpot et al 2015). The candidate gene in this location that is associated with palate development is the transcription factor MN1.…”

Section: Mouse and Human Genetics Identify Candidate Signaling Pathwamentioning

confidence: 99%

See 1 more Smart Citation

Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion

et al. 2015

View full text Add to dashboard Cite

It is essential to complete palate closure at the correct time during fetal development, otherwise a serious malformation, cleft palate, will ensue. The steps in palate formation in humans take place between the 7th and 12th week and consist of outgrowth of palatal shelves from the paired maxillary prominences, reorientation of the shelves from vertical to horizontal, apposition of the medial surfaces, formation of a bilayered seam, degradation of the seam and bridging of mesenchyme. However, in the soft palate, the mechanism of closure is unclear. In previous studies it is possible to find support for both fusion and the alternative mechanism of merging. Here we densely sample the late embryonic-early fetal period between 54 and 74 days post-conception to determine the timing and mechanism of soft palate closure. We found the epithelial seam extends throughout the soft palates of 57-day specimens. Cytokeratin antibody staining detected the medial edge epithelium and distinguished clearly that cells in the midline retained their epithelial character. Compared with the hard palate, the epithelium is more rapidly degraded in the soft palate and only persists in the most posterior regions at 64 days. Our results are consistent with the soft palate following a developmentally more rapid program of fusion than the hard palate. Importantly, the two regions of the palate appear to be independently regulated and have their own internal clocks regulating the timing of seam removal. Considering data from human genetic and mouse studies, distinct anterior-posterior signaling mechanisms are likely to be at play in the human fetal palate.

show abstract

“…; Breckpot et al. ). The candidate gene in this location that is associated with palate development is the transcription factor MN1.…”

Section: Discussionmentioning

confidence: 98%

Section: Mouse and Human Genetics Identify Candidate Signaling Pathwamentioning

confidence: 99%

Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion

et al. 2015

View full text Add to dashboard Cite

show abstract

“…MN1 gene comprises only two exons and encodes a transcriptional co‐regulator with poorly defined molecular functions, previously implicated in acute myeloid leukemia and craniofacial anomalies (Heuser et al, 2006; Hoebel et al, 2017; Liu et al, 2008; Meester‐Smoor et al, 2005). Although 22q12.1 deletions involving MN1 gene has been reported in patients with variable developmental delay and facial anomalies (Beck et al, 2015; Breckpot et al, 2016), a distinct phenotype in patients with MN1 C‐terminal truncating mutations enable the rare condition to be recognizable as a discrete clinical entity (Mak, Doherty, et al, 2020; Miyake et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Novel truncating variant of MN1 penultimate exon identified in a Chinese patient with newly recognized MN1 C‐terminal truncation syndrome: Case report and literature review

Zhao

Shu

Zhang

et al. 2021

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

MN1 C‐terminal truncation (MCTT) syndrome is a newly recognized neurodevelopmental disorder due to heterozygous gain‐of‐function C‐terminal truncating mutations clustering in the last or penultimate exon of MN1 gene (MIM: 156100). Up to date, only 25 affected patients have been reported. Here, we report a 2‐year‐old Chinese girl with MCTT syndrome. The girl presented with the characteristic features of the syndrome, including global developmental delay (GDD), facial dysmorphism and hearing impairment. Notably, the patient did not have other frequently observed symptoms such as hypotonia, cranial or brain abnormalities, indicating variability of the phenotype of patients with MN1 C‐terminal truncating mutations. Trio whole‐exome sequencing revealed a novel de novo heterozygous nonsense variant in the extreme 3′ region of penultimate exon of MN1 (NM_002430.3: c.3743G > A, p.Trp1248*). This rare truncating variant was classified as pathogenic due to its predicted gain‐of‐function effect, given that the gain‐of‐function MN1 truncating variants producing C‐terminally truncated proteins have been confirmed to cause the recognizable syndrome. Additionally, a systematic review of previously reported MN1 variants including C‐terminal truncating variants and N‐terminal truncating variants shows that different location of MN1 truncating variants causes two distinct clinical subtypes. To our knowledge, this is the first reported case of MCTT syndrome caused by a novel MN1 C‐terminal truncating variant in a Chinese population, which enriched the mutation spectrum of MN1 gene and further supporting the association of the novel MCTT syndrome with MN1 C‐terminal truncating variants.

show abstract

“…MN1 has been implicated in brain and craniofacial development in mice and humans. [7][8][9] In mice, Mn1 is strongly expressed in the midbrain, hindbrain, and craniofacial mesenchyme at embryonic day 9.5 (E9.5) and in all the prominences of the developing face by E10.5. 9 Mn1 exhibits notable differential expression along the anteroposterior axis of the developing second plate during palatal outgrowth.…”

Section: Introductionmentioning

confidence: 99%

“…10 In humans, at least nine individuals with a heterozygous deletion involving MN1 have been reported, and all have orofacial features, including a cleft palate. 7,11,12 However, because other genes were also deleted in these individuals, it remains unknown whether MN1 deletion alone affects human development.…”

Section: Introductionmentioning

confidence: 99%

Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities

Miyake

Takahashi

Nakamura

et al. 2020

The American Journal of Human Genetics

View full text Add to dashboard Cite

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.

show abstract

Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate

Cited by 10 publications

References 33 publications

Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion

Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion

Novel truncating variant of MN1 penultimate exon identified in a Chinese patient with newly recognized MN1 C‐terminal truncation syndrome: Case report and literature review

Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities

Contact Info

Product

Resources

About