Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Rocker, Nina De; Vergult, Sarah; Koolen, David A.; Jacobs, Eva; Hoischen, Alexander; Zeesman, Susan; Bang, Birgitte; Béna, Frédérique; Bockaert, Nele; Bongers, Ernie M.H.F.; Ravel, Thomy de; Devriendt, Koenraad; Giglio, Sabrina; Faivre, Laurence; Joss, Shelagh; Maas, Saskia M.; Marle, Nathalie; Novara, Francesca; Nowaczyk, Małgorzata J.M.; Peeters, Hilde; Polstra, Abeltje M.; Roelens, Filip; Rosenberg, Carla; Thévenon, Julien; Tümer, Zeynep; Vanhauwaert, Suzanne; Varvagiannis, Konstantinos; Willaert, Andy; Willemsen, Marjolein H.; Willems, Marjolaine; Zuffardi, Orsetta; Coucke, Paul; Speleman, Frank; Eichler, Evan E.; Kleefstra, Tjitske; Menten, Björn

doi:10.1038/gim.2014.124

Cited by 49 publications

(76 citation statements)

References 25 publications

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“…In 2012, a de novo MYT1L splice site mutation was identified as part of a larger study in a girl with ID, autistic features, normal growth, and mild dysmorphism (de Ligt et al, ). After three publications on seven more individuals with microdeletions encompassing MYT1L and global DD/ID, behavioral difficulties/hyperactivity and overweight/obesity (Bonaglia et al, ; Doco‐Fenzy et al, ; Rio et al, ), de Rocker and colleagues published an extensive study on 22 individuals bearing either chromosomal aberrations or SNVs affecting MYT1L (De Rocker et al, ). Seventeen of these 22 individuals presented with obesity/overweight.…”

Section: Discussionmentioning

confidence: 99%

Nine newly identified individuals refine the phenotype associated with MYT1L mutations

Windheuser

Becker

Cremer

et al. 2020

American J of Med Genetics Pt A

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Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainlycausative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was Isabelle C. Windheuser, Jessica Becker, and Kirsten Cremer contributed equally as first authors. Roberto Colombo, Maja Hempel, and Hartmut Engels contributed equally as senior authors.

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Section: Discussionmentioning

confidence: 99%

Nine newly identified individuals refine the phenotype associated with MYT1L mutations

Windheuser

Becker

Cremer

et al. 2020

American J of Med Genetics Pt A

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“…A role for MYT1L in neural development is further supported by the identification of MYT1L mutations in patients diagnosed with various neurodevelopmental disorders. The identification of mutations on chromosome band 2p25.3 disrupting the MYT1L gene in patients with mild to moderate intellectual disability and speech delay (Bonaglia et al , 2014; de Ligt et al , 2012; De Rocker et al , 2015; Mayo et al , 2015; Stevens et al , 2011) provided the first links between haploinsufficiency of MYT1L and intellectual disability (De Rocker et al , 2015). MYT1L mutations have also been associated with diseases, such as schizophrenia (Lee et al , 2012; Vrijenhoek et al , 2008), autism (De Rubeis et al , 2014; Meyer et al , 2012) and major depressive disorder (Wang et al , 2010).…”

Section: Introductionmentioning

confidence: 99%

Associations of the Intellectual Disability Gene MYT1L with Helix–Loop–Helix Gene Expression, Hippocampus Volume and Hippocampus Activation During Memory Retrieval

Kepa

Medina

Erk

et al. 2017

Neuropsychopharmacol.

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The fundamental role of the brain-specific myelin transcription factor 1-like (MYT1L) gene in cases of intellectual disability and in the aetiology of neurodevelopmental disorders is increasingly recognised. Yet, its function remains under-investigated. Here, we identify a network of helix-loop-helix (HLH) transcriptional regulators controlled by MYT1L, as indicated by our analyses in human neural stem cells and in the human brain. Using cell-based knockdown approaches and microarray analyses we found that (i) MYT1L is required for neuronal differentiation and identified ID1, a HLH inhibitor of premature neurogenesis, as a target. (2) While MYT1L prevented expression of ID1, it induced expression of a large number of terminal differentiation genes. (3) Consistently, expression of MYT1L in the human brain coincided with neuronal maturation and inversely correlated with that of ID1 and ID3 throughout the lifespan. (4) Genetic polymorphisms that reduced expression of MYT1L in the hippocampus resulted in increased expression of ID1 and ID3, decreased levels of the proneural basic HLH (bHLH) transcriptional regulators TCF4 and NEUROD6 and decreased expression of genes involved in long-term potentiation and synaptic transmission, cancer and neurodegeneration. Furthermore, our neuroimaging analyses indicated that MYT1L expression associated with hippocampal volume and activation during episodic memory recall, as measured by blood-oxygen-level dependent (BOLD) signals. Overall, our findings suggest that MYT1L influences memory-related processes by controlling a neuronal proliferation/differentiation switch of ID-bHLH factors.

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“…It has been observed that peroxidase activity is significantly decreased by regular vomiting [Schlueter et al, 2012], and proteolytic enzymes seem to be relevant for the initiation and progression of dental erosion directly after vomiting, maybe by both hydrolysis of demineralized dentine structures as well as modulation of the pellicle layer [Schlueter et al, 2012]. MYT1L has been reported to be involved in neural development, weight problems of childhood onset and a clinical phenotype of dysmorphic features [Stevens et al, 2011;De Rocker et al, 2015]. Interestingly, a suggestively associated polymorphism in a GWAS of dental caries was observed close to the abovementioned region [Shaffer et al, 2013].…”

Section: Gwas On the Whole Samplementioning

confidence: 99%

Genome-Wide Association Study of Erosive Tooth Wear in a Finnish Cohort

et al. 2018

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Erosive tooth wear is defined as irreversible loss of dental tissues due to intrinsic or extrinsic acids, exacerbated by mechanical forces. Recent studies have suggested a higher prevalence of erosive tooth wear in males, as well as a genetic contribution to susceptibility to erosive tooth wear. Our aim was to examine erosive tooth wear by performing a genome-wide association study (GWAS) in a sample of the Northern Finland Birth Cohort 1966 (n = 1,962). Erosive tooth wear was assessed clinically using the basic erosive wear examination. A GWAS was performed for the whole sample as well as separately for males and females. We identified one genome-wide significant signal (rs11681214) in the GWAS of the whole sample near the genes PXDN and MYT1L. When the sample was stratified by sex, the strongest genome-wide significant signals were observed in or near the genes FGFR1, C8orf86, CDH4, SCD5, F2R, and ING1. Additionally, multiple suggestive association signals were detected in all GWASs performed. Many of the signals were in or near the genes putatively related to oral environment or tooth development, and some were near the regions considered to be associated with dental caries, such as 2p24, 4q21, and 13q33. Replications of these associations in other samples, as well as experimental studies to determine the biological functions of associated genetic variants, are needed.

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Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Abstract: Conclusion:Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.

Cited by 49 publications

References 25 publications

Nine newly identified individuals refine the phenotype associated with MYT1L mutations

Nine newly identified individuals refine the phenotype associated with MYT1L mutations

Associations of the Intellectual Disability Gene MYT1L with Helix–Loop–Helix Gene Expression, Hippocampus Volume and Hippocampus Activation During Memory Retrieval

Genome-Wide Association Study of Erosive Tooth Wear in a Finnish Cohort

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