publication . Other literature type . Article . 2017

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus

Blanchet, Patricia; Bebin, Martina; Bruet, Shaam; Cooper, Gregory M.; Thompson, Michelle L.; Duban-Bedu, Benedicte; Gerard, Benedicte; Piton, Amelie; Suckno, Sylvie; Deshpande, Charu; ...
  • Published: 31 Aug 2017
  • Publisher: Public Library of Science (PLoS)
  • Country: United Kingdom
Abstract
Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p...
Subjects
free text keywords: Genetics, QH426-470, Research Article, Biology and Life Sciences, Physiology, Physiological Parameters, Body Weight, Obesity, Medicine and Health Sciences, Gene Expression, Research and Analysis Methods, Experimental Organism Systems, Model Organisms, Zebrafish, Animal Models, Organisms, Animals, Vertebrates, Fishes, Osteichthyes, Anatomy, Brain, Hypothalamus, Psychology, Developmental Psychology, Pervasive Developmental Disorders, Autism Spectrum Disorder, Autism, Social Sciences, Neuroscience, Developmental Neuroscience, Neurodevelopmental Disorders, Neurology, Computational Biology, Genome Analysis, Gene Ontologies, Genomics, Biochemistry, Neurochemistry, Neurochemicals, Oxytocin, Hormones, Peptide Hormones, Proteins, DNA-binding proteins
Funded by
NIH| Genomic Diagnosis in Children with Developmental Delay
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 4UM1HG007301-04
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Integrative interpretation of the organismal consequences of non-coding variation
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA197139-03
  • Funding stream: NATIONAL CANCER INSTITUTE
,
WT| Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 098051
  • Funding stream: Cellular and Molecular Neuroscience
Communities
Neuroinformatics
45 references, page 1 of 3

1. Emerson E, Hatton C, Baines S, Robertson J. The physical health of British Adults with intellectual disability: cross sectional study. Int J Equity Heatlh. 2016; 15: 11.

2. Van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015; 161(1): 119±132. https://doi.org/10.1016/j.cell.2015.03.008 PMID: 25815990 [OpenAIRE]

3. Rosenfeld JA, Patel A. Chromosomal microarrays: understanding genetics of neurodevelopmental disorders and congenital anomalies. J Pediatr Genet. 2017; 6 (1): 42±50. https://doi.org/10.1055/s-0036- 1584306 PMID: 28180026

Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, Kogelenberg MV, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015; 385 (9975): 1305±1314. https://doi.org/10.1016/S0140-6736(14)61705-0 PMID: 25529582

5. Kaur Y, de Souza RJ, Gibson WT, Meyre D. A systematic review of genetic syndromes with obesity. Obes Rev. 2017; https://doi.org/10.1111/obr.12531 PMID: 28346723

6. Ramachandrappa S, Raimondo A, Cali AM, Keogh JM, Henning E, Saeed S, et al. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. J Clin Invest. 2013; 123 (7): 3042±3050. https://doi.org/10.1172/JCI68016 PMID: 23778139 [OpenAIRE]

Wentzel C, Lynch SA, Stattin EL, Sharkey FH, Anneren G, Thuresson AC. Interstitial deletions at 6q14.1-q15 associated with obesity, developmental delay and a distinct clinical phenotype. Mol Syndromol. 2010; 1 (2): 75±81. https://doi.org/10.1159/000314025 PMID: 21045960 [OpenAIRE]

8. Tolson KP, Gemelli T, Gautron L, Elmquist JK, Zinn AR, Kublaoui BM. Postnatal SIM1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. J Neurosci 2010; 30(10): 3803±3812. https://doi.org/10.1523/JNEUROSCI.5444-09.2010 PMID: 20220015 [OpenAIRE]

9. Michaud JL, Bouchre F, Melnyk A, Gauthier F, Goshu E, Levy E, et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 2001; 10 (14): 1465±1473. PMID: 11448938 [OpenAIRE]

10. De Rocker N, Vergult S, Koolen D, Jacobs E, Hoischen A, Zeesman S, et al. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity. Genet Med. 2015; 17 (6): 460±466. https://doi.org/10.1038/gim.2014.124 PMID: 25232846

11. Bonaglia MC, Giorda R, Zanina S. A new patient with a terminal de novo deletion of 1.9 Mb associated with early onset obesity, intellectual disabilities and hyperkinetic disorder. Mol Cytogenet. 2014; 7:53. https://doi.org/10.1186/1755-8166-7-53 PMID: 25126114 [OpenAIRE]

12. Doco-Fenzy M, Leroy C, Schneider A, Petit F, Delrue MA, Andrieux J, et al. Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18 and MYT1L genes. Eur J Hum Genet 2014; 22 (4): 471±479. https://doi.org/10.1038/ejhg.2013.189 PMID: 24129437

13. Rio M, Royer G, Gobin S, de Blois MC, Oziliou C, Bernheim A, et al. Monozygotic twins discordant for submicroscopic chromosomal anomalies in 2p25.3 region detected by array CGH. Clin Genet 2013; 84 (1): 31±36. https://doi.org/10.1111/cge.12036 PMID: 23061379

14. Stevens SJC, van Ravenswaaij-Arts CMA, Jannsen JWH, Wassink-Ruiter JSK, van Essen AJ, Dijkhuizen T, et al. MYT1L is a candidate gene for intellectual disability in patients with 2p25.3 (2pter) deletions. Am J Med Genet. 2011; 155A(11): 2739±2745. https://doi.org/10.1002/ajmg.a.34274 PMID: 21990140 [OpenAIRE]

15. Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, et al. Homozygous mutations in PXDN cause congenital cataract, corneal opacity and developmental glaucoma Am J Human Genet 2011; 89 (3): 464±473.

45 references, page 1 of 3
Abstract
Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p...
Subjects
free text keywords: Genetics, QH426-470, Research Article, Biology and Life Sciences, Physiology, Physiological Parameters, Body Weight, Obesity, Medicine and Health Sciences, Gene Expression, Research and Analysis Methods, Experimental Organism Systems, Model Organisms, Zebrafish, Animal Models, Organisms, Animals, Vertebrates, Fishes, Osteichthyes, Anatomy, Brain, Hypothalamus, Psychology, Developmental Psychology, Pervasive Developmental Disorders, Autism Spectrum Disorder, Autism, Social Sciences, Neuroscience, Developmental Neuroscience, Neurodevelopmental Disorders, Neurology, Computational Biology, Genome Analysis, Gene Ontologies, Genomics, Biochemistry, Neurochemistry, Neurochemicals, Oxytocin, Hormones, Peptide Hormones, Proteins, DNA-binding proteins
Funded by
NIH| Genomic Diagnosis in Children with Developmental Delay
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 4UM1HG007301-04
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Integrative interpretation of the organismal consequences of non-coding variation
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA197139-03
  • Funding stream: NATIONAL CANCER INSTITUTE
,
WT| Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 098051
  • Funding stream: Cellular and Molecular Neuroscience
Communities
Neuroinformatics
45 references, page 1 of 3

1. Emerson E, Hatton C, Baines S, Robertson J. The physical health of British Adults with intellectual disability: cross sectional study. Int J Equity Heatlh. 2016; 15: 11.

2. Van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015; 161(1): 119±132. https://doi.org/10.1016/j.cell.2015.03.008 PMID: 25815990 [OpenAIRE]

3. Rosenfeld JA, Patel A. Chromosomal microarrays: understanding genetics of neurodevelopmental disorders and congenital anomalies. J Pediatr Genet. 2017; 6 (1): 42±50. https://doi.org/10.1055/s-0036- 1584306 PMID: 28180026

Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, Kogelenberg MV, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015; 385 (9975): 1305±1314. https://doi.org/10.1016/S0140-6736(14)61705-0 PMID: 25529582

5. Kaur Y, de Souza RJ, Gibson WT, Meyre D. A systematic review of genetic syndromes with obesity. Obes Rev. 2017; https://doi.org/10.1111/obr.12531 PMID: 28346723

6. Ramachandrappa S, Raimondo A, Cali AM, Keogh JM, Henning E, Saeed S, et al. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. J Clin Invest. 2013; 123 (7): 3042±3050. https://doi.org/10.1172/JCI68016 PMID: 23778139 [OpenAIRE]

Wentzel C, Lynch SA, Stattin EL, Sharkey FH, Anneren G, Thuresson AC. Interstitial deletions at 6q14.1-q15 associated with obesity, developmental delay and a distinct clinical phenotype. Mol Syndromol. 2010; 1 (2): 75±81. https://doi.org/10.1159/000314025 PMID: 21045960 [OpenAIRE]

8. Tolson KP, Gemelli T, Gautron L, Elmquist JK, Zinn AR, Kublaoui BM. Postnatal SIM1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. J Neurosci 2010; 30(10): 3803±3812. https://doi.org/10.1523/JNEUROSCI.5444-09.2010 PMID: 20220015 [OpenAIRE]

9. Michaud JL, Bouchre F, Melnyk A, Gauthier F, Goshu E, Levy E, et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 2001; 10 (14): 1465±1473. PMID: 11448938 [OpenAIRE]

10. De Rocker N, Vergult S, Koolen D, Jacobs E, Hoischen A, Zeesman S, et al. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity. Genet Med. 2015; 17 (6): 460±466. https://doi.org/10.1038/gim.2014.124 PMID: 25232846

11. Bonaglia MC, Giorda R, Zanina S. A new patient with a terminal de novo deletion of 1.9 Mb associated with early onset obesity, intellectual disabilities and hyperkinetic disorder. Mol Cytogenet. 2014; 7:53. https://doi.org/10.1186/1755-8166-7-53 PMID: 25126114 [OpenAIRE]

12. Doco-Fenzy M, Leroy C, Schneider A, Petit F, Delrue MA, Andrieux J, et al. Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18 and MYT1L genes. Eur J Hum Genet 2014; 22 (4): 471±479. https://doi.org/10.1038/ejhg.2013.189 PMID: 24129437

13. Rio M, Royer G, Gobin S, de Blois MC, Oziliou C, Bernheim A, et al. Monozygotic twins discordant for submicroscopic chromosomal anomalies in 2p25.3 region detected by array CGH. Clin Genet 2013; 84 (1): 31±36. https://doi.org/10.1111/cge.12036 PMID: 23061379

14. Stevens SJC, van Ravenswaaij-Arts CMA, Jannsen JWH, Wassink-Ruiter JSK, van Essen AJ, Dijkhuizen T, et al. MYT1L is a candidate gene for intellectual disability in patients with 2p25.3 (2pter) deletions. Am J Med Genet. 2011; 155A(11): 2739±2745. https://doi.org/10.1002/ajmg.a.34274 PMID: 21990140 [OpenAIRE]

15. Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, et al. Homozygous mutations in PXDN cause congenital cataract, corneal opacity and developmental glaucoma Am J Human Genet 2011; 89 (3): 464±473.

45 references, page 1 of 3
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