11 results on '"van Haelst, Mieke M"'
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2. De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions
- Author
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Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Fregeau, Brieana, Kim, Bum Jun, Hernández-García, Andrés, Jordan, Valerie K, Cho, Megan T, Schnur, Rhonda E, Monaghan, Kristin G, Juusola, Jane, Rosenfeld, Jill A, Bhoj, Elizabeth, Zackai, Elaine H, Sacharow, Stephanie, Barañano, Kristin, Bosch, Daniëlle G M, de Vries, Bert B A, Lindstrom, Kristin, Schroeder, Audrey, James, Philip, Kulch, Peggy, Lalani, Seema R, van Haelst, Mieke M, van Gassen, Koen L I, van Binsbergen, Ellen, Barkovich, A James, Scott, Daryl A, Sherr, Elliott H, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Fregeau, Brieana, Kim, Bum Jun, Hernández-García, Andrés, Jordan, Valerie K, Cho, Megan T, Schnur, Rhonda E, Monaghan, Kristin G, Juusola, Jane, Rosenfeld, Jill A, Bhoj, Elizabeth, Zackai, Elaine H, Sacharow, Stephanie, Barañano, Kristin, Bosch, Daniëlle G M, de Vries, Bert B A, Lindstrom, Kristin, Schroeder, Audrey, James, Philip, Kulch, Peggy, Lalani, Seema R, van Haelst, Mieke M, van Gassen, Koen L I, van Binsbergen, Ellen, Barkovich, A James, Scott, Daryl A, and Sherr, Elliott H
- Published
- 2016
3. A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology
- Author
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Migliavacca, Eugenia, Golzio, Christelle, Männik, Katrin, Blumenthal, Ian, Oh, Edwin C., Harewood, Louise, Kosmicki, Jack A., Loviglio, Maria Nicla, Giannuzzi, Giuliana, Hippolyte, Loyse, Maillard, Anne M., Alfaiz, Ali Abdullah, Witwicki, Robert, Didelot, Gérard, Van Der Werf, Ilse, Alfaiz, Ali A., Zazhytska, Marianna, Chrast, Jacqueline, Macé, Aurélien, Bergmann, Sven, Kutalik, Zoltan, Siffredi, Vanessa, Zufferey, Flore, Martinet, Danielle, Bena, Frédérique, Rauch, Anita, Bouquillon, Sonia, Delobel, Bruno, Boute, Odile, Duban-Bedu, Bénédicte, Le Caignec, Cédric, Isidor, Bertrand, Chiesa, Jean, Keren, Boris, Gilbert-Dussardier, Brigitte, Touraine, Renaud, Campion, Dominique, Thambo, Caroline Rooryck, Mathieu-Dramard, Michèle, Plessis, Ghislaine, Kooy, Frank, Peeters, Hilde, Ounap, Katrin, Vulto-Van Silfhout, Anneke T., De Vries, Bert B., Van Binsbergen, Ellen, Nordgren, Ann, Mucciolo, Mafalda, Renieri, Alessandra, Rajcan-Separovic, Evica, Philipps, John A., Ellis, Richard J., Van Haelst, Mieke M., Andrieux, Joris, Gusella, James F., Daly, Mark J., Beckmann, Jacques S., Jacquemont, Sébastien, Talkowski, Michael E., Katsanis, Nicholas, Reymond, Alexandre, Migliavacca, Eugenia, Golzio, Christelle, Männik, Katrin, Blumenthal, Ian, Oh, Edwin C., Harewood, Louise, Kosmicki, Jack A., Loviglio, Maria Nicla, Giannuzzi, Giuliana, Hippolyte, Loyse, Maillard, Anne M., Alfaiz, Ali Abdullah, Witwicki, Robert, Didelot, Gérard, Van Der Werf, Ilse, Alfaiz, Ali A., Zazhytska, Marianna, Chrast, Jacqueline, Macé, Aurélien, Bergmann, Sven, Kutalik, Zoltan, Siffredi, Vanessa, Zufferey, Flore, Martinet, Danielle, Bena, Frédérique, Rauch, Anita, Bouquillon, Sonia, Delobel, Bruno, Boute, Odile, Duban-Bedu, Bénédicte, Le Caignec, Cédric, Isidor, Bertrand, Chiesa, Jean, Keren, Boris, Gilbert-Dussardier, Brigitte, Touraine, Renaud, Campion, Dominique, Thambo, Caroline Rooryck, Mathieu-Dramard, Michèle, Plessis, Ghislaine, Kooy, Frank, Peeters, Hilde, Ounap, Katrin, Vulto-Van Silfhout, Anneke T., De Vries, Bert B., Van Binsbergen, Ellen, Nordgren, Ann, Mucciolo, Mafalda, Renieri, Alessandra, Rajcan-Separovic, Evica, Philipps, John A., Ellis, Richard J., Van Haelst, Mieke M., Andrieux, Joris, Gusella, James F., Daly, Mark J., Beckmann, Jacques S., Jacquemont, Sébastien, Talkowski, Michael E., Katsanis, Nicholas, and Reymond, Alexandre
- Published
- 2015
4. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes
- Author
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Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, Markello, Thomas C, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, and Markello, Thomas C
- Published
- 2015
5. A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology
- Author
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Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Migliavacca, Eugenia, Golzio, Christelle, Männik, Katrin, Blumenthal, Ian, Oh, Edwin C., Harewood, Louise, Kosmicki, Jack A., Loviglio, Maria Nicla, Giannuzzi, Giuliana, Hippolyte, Loyse, Maillard, Anne M., Alfaiz, Ali Abdullah, Witwicki, Robert, Didelot, Gérard, Van Der Werf, Ilse, Alfaiz, Ali A., Zazhytska, Marianna, Chrast, Jacqueline, Macé, Aurélien, Bergmann, Sven, Kutalik, Zoltan, Siffredi, Vanessa, Zufferey, Flore, Martinet, Danielle, Bena, Frédérique, Rauch, Anita, Bouquillon, Sonia, Delobel, Bruno, Boute, Odile, Duban-Bedu, Bénédicte, Le Caignec, Cédric, Isidor, Bertrand, Chiesa, Jean, Keren, Boris, Gilbert-Dussardier, Brigitte, Touraine, Renaud, Campion, Dominique, Thambo, Caroline Rooryck, Mathieu-Dramard, Michèle, Plessis, Ghislaine, Kooy, Frank, Peeters, Hilde, Ounap, Katrin, Vulto-Van Silfhout, Anneke T., De Vries, Bert B., Van Binsbergen, Ellen, Nordgren, Ann, Mucciolo, Mafalda, Renieri, Alessandra, Rajcan-Separovic, Evica, Philipps, John A., Ellis, Richard J., Van Haelst, Mieke M., Andrieux, Joris, Gusella, James F., Daly, Mark J., Beckmann, Jacques S., Jacquemont, Sébastien, Talkowski, Michael E., Katsanis, Nicholas, Reymond, Alexandre, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Migliavacca, Eugenia, Golzio, Christelle, Männik, Katrin, Blumenthal, Ian, Oh, Edwin C., Harewood, Louise, Kosmicki, Jack A., Loviglio, Maria Nicla, Giannuzzi, Giuliana, Hippolyte, Loyse, Maillard, Anne M., Alfaiz, Ali Abdullah, Witwicki, Robert, Didelot, Gérard, Van Der Werf, Ilse, Alfaiz, Ali A., Zazhytska, Marianna, Chrast, Jacqueline, Macé, Aurélien, Bergmann, Sven, Kutalik, Zoltan, Siffredi, Vanessa, Zufferey, Flore, Martinet, Danielle, Bena, Frédérique, Rauch, Anita, Bouquillon, Sonia, Delobel, Bruno, Boute, Odile, Duban-Bedu, Bénédicte, Le Caignec, Cédric, Isidor, Bertrand, Chiesa, Jean, Keren, Boris, Gilbert-Dussardier, Brigitte, Touraine, Renaud, Campion, Dominique, Thambo, Caroline Rooryck, Mathieu-Dramard, Michèle, Plessis, Ghislaine, Kooy, Frank, Peeters, Hilde, Ounap, Katrin, Vulto-Van Silfhout, Anneke T., De Vries, Bert B., Van Binsbergen, Ellen, Nordgren, Ann, Mucciolo, Mafalda, Renieri, Alessandra, Rajcan-Separovic, Evica, Philipps, John A., Ellis, Richard J., Van Haelst, Mieke M., Andrieux, Joris, Gusella, James F., Daly, Mark J., Beckmann, Jacques S., Jacquemont, Sébastien, Talkowski, Michael E., Katsanis, Nicholas, and Reymond, Alexandre
- Published
- 2015
6. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes
- Author
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Genetica Groep Van Haaften, Child Health, Medische Fysiologie, Circulatory Health, Hubrecht Institute with UMC, Genetica Klinische Genetica, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, Markello, Thomas C, Genetica Groep Van Haaften, Child Health, Medische Fysiologie, Circulatory Health, Hubrecht Institute with UMC, Genetica Klinische Genetica, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, and Markello, Thomas C
- Published
- 2015
7. PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response.
- Author
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Deb, Wallid, Rosenfelt, Cory, Vignard, Virginie, Papendorf, Jonas Johannes, Möller, Sophie, Wendlandt, Martin, Studencka-Turski, Maja, Cogné, Benjamin, Besnard, Thomas, Ruffier, Léa, Toutain, Bérénice, Poirier, Léa, Cuinat, Silvestre, Kritzer, Amy, Crunk, Amy, diMonda, Janette, Vengoechea, Jaime, Mercier, Sandra, Kleinendorst, Lotte, and van Haelst, Mieke M.
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TYPE I interferons , *HUMAN biology , *PHENOTYPES , *INTERFERONS , *OBESITY , *DROSOPHILA melanogaster , *PROTEASOMES - Abstract
Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1 , PSMC1 , PSMC3 , or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be recapitulated in Drosophila melanogaster with depletion of the PMSD11 ortholog Rpn6 , which compromised reversal learning. Our investigations in subject samples further revealed that PSMD11 loss of function resulted in impaired 26S proteasome assembly and the acquisition of a persistent type I interferon (IFN) gene signature, mediated by the integrated stress response (ISR) protein kinase R (PKR). In summary, these data identify PSMD11 as an additional member of the growing family of genes associated with neurodevelopmental proteasomopathies and provide insights into proteasomal biology in human health. [Display omitted] Deb et al. have identified PSMD11 , which encodes a proteasome subunit, as a causative factor for a neurodevelopmental disorder. Their investigations involving clinical phenotype analysis and proband-derived cell lines as well as animal and cellular models have established an association between PSMD11 variants and impaired learning abilities, obesity, and auto-inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
8. Successful naltrexone-bupropion treatment after several treatment failures in a patient with severe monogenic obesity.
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Welling MS, Mohseni M, van der Valk ES, van Hagen JM, Burgerhart JS, van Haelst MM, and van Rossum EFC
- Abstract
We describe the therapeutic journey of a 33-year-old patient with early-onset obesity (BMI 56.7 kg/m
2 ) and hyperphagia due to a likely pathogenic heterozygous melanocortin-4 receptor ( MC4R ) gene variant. She was unsuccessfully treated with several intensive lifestyle interventions, gastric bypass surgery (-40 kg weight loss, followed by +39.8 kg weight regain), liraglutide 3 mg (-3.8% weight loss with sustained hyperphagia), and metformin treatment. However, naltrexone-bupropion treatment led to -48.9 kg (-26.7%) weight loss, of which -39.9 kg (-38.3%) was fat mass, in 17 months of treatment. Importantly, she reported improved hyperphagia and quality of life. We describe the potential beneficial effects of naltrexone-bupropion on weight, hyperphagia, and quality of life in a patient with genetic obesity. This extensive journey shows that various anti-obesity agents can be initiated, subsequently terminated when ineffective and substituted with other anti-obesity agents to identify the most efficient anti-obesity treatment., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)- Published
- 2023
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9. De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions.
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Fregeau B, Kim BJ, Hernández-García A, Jordan VK, Cho MT, Schnur RE, Monaghan KG, Juusola J, Rosenfeld JA, Bhoj E, Zackai EH, Sacharow S, Barañano K, Bosch DGM, de Vries BBA, Lindstrom K, Schroeder A, James P, Kulch P, Lalani SR, van Haelst MM, van Gassen KLI, van Binsbergen E, Barkovich AJ, Scott DA, and Sherr EH
- Subjects
- Animals, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 1, Female, Humans, Infant, Male, Mice, Phenotype, Prognosis, Abnormalities, Multiple etiology, Carrier Proteins genetics, Chromosome Disorders etiology, Developmental Disabilities etiology, Haploinsufficiency genetics, Mutation genetics
- Abstract
Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
10. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
- Author
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Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, Huang H, Valkanas E, Pusey B, Schanze D, Venselaar H, Vulto-van Silfhout AT, Wolfe LA, Tifft CJ, Zerfas PM, Zambruno G, Kariminejad A, Sabbagh-Kermani F, Lee J, Tsokos MG, Lee CC, Ferraz V, da Silva EM, Stevens CA, Roche N, Bartsch O, Farndon P, Bermejo-Sanchez E, Brooks BP, Maduro V, Dallapiccola B, Ramos FJ, Chung HY, Le Caignec C, Martins F, Jacyk WK, Mazzanti L, Brunner HG, Bakkers J, Lin S, Malicdan MC, Boerkoel CF, Gahl WA, de Vries BB, van Haelst MM, Zenker M, and Markello TC
- Subjects
- Abnormalities, Multiple pathology, Amino Acid Sequence, Animals, Base Sequence, Chromatin Immunoprecipitation, Exome genetics, Eye Abnormalities pathology, Eyelid Diseases pathology, HeLa Cells, Hirsutism pathology, Humans, Hypertelorism pathology, Hypertrichosis pathology, Macrostomia pathology, Microscopy, Electron, Molecular Sequence Data, Mutation, Missense genetics, Protein Conformation, Repressor Proteins chemistry, Sequence Analysis, DNA, Skin Abnormalities pathology, Twist-Related Protein 1 chemistry, Zebrafish, Abnormalities, Multiple genetics, Eye Abnormalities genetics, Eyelid Diseases genetics, Hirsutism genetics, Hypertelorism genetics, Hypertrichosis genetics, Macrostomia genetics, Models, Molecular, Phenotype, Repressor Proteins genetics, Skin Abnormalities genetics, Twist-Related Protein 1 genetics
- Abstract
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
11. A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.
- Author
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Migliavacca E, Golzio C, Männik K, Blumenthal I, Oh EC, Harewood L, Kosmicki JA, Loviglio MN, Giannuzzi G, Hippolyte L, Maillard AM, Alfaiz AA, van Haelst MM, Andrieux J, Gusella JF, Daly MJ, Beckmann JS, Jacquemont S, Talkowski ME, Katsanis N, and Reymond A
- Subjects
- Animals, Brain, Child, Child Development Disorders, Pervasive pathology, Chromosome Deletion, Ciliary Body metabolism, Ciliary Body pathology, Gene Expression Regulation, Humans, Mice, Potassium Channels, Voltage-Gated genetics, Schizophrenia pathology, Transcriptome, Zebrafish, Zebrafish Proteins genetics, Child Development Disorders, Pervasive genetics, Chromosomes, Human, Pair 16 genetics, DNA Copy Number Variations genetics, Schizophrenia genetics
- Abstract
The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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