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Angela M. Kaindl - One of the best experts on this subject based on the ideXlab platform.
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congenital microcephaly linked CDK5RAP2 affects eye development
Annals of Human Genetics, 2020Co-Authors: Sami Zaqout, Ethiraj Ravindran, Gisela Stoltenburgdidinger, Angela M. KaindlAbstract:Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal recessive primary microcephaly type 3 (MCPH3). MCPH is characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. Only recently, congenital cataracts were reported in four patients of one pedigree with MCPH3. Given the lack of a further pedigree with this phenotype, it remained unclear whether this was a true causal relationship. Here we support the link between CDK5RAP2 and eye development by showing that most CDK5RAP2 mutant mice (an/an) exhibit eye malformations ranging from reduced size of one or both eyes (microphthalmia) to total absence of both eyes (anophthalmia). We also detected increased apoptosis in the an/an retinal progenitor cells associated with more mitotic cells. This indicates an important role of CDK5RAP2 in physiologic eye development.
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Altered inhibition and excitation in neocortical circuits in congenital microcephaly
Neurobiology of Disease, 2019Co-Authors: Sami Zaqout, Kathrin Blaesius, Yuan-ju Wu, Nadine Kraemer, Lena-luise Becker, Marta Rosário, Christian Rosenmund, Ulf Strauss, Angela M. KaindlAbstract:Abstract Congenital microcephaly is highly associated with intellectual disability. Features of autosomal recessive primary microcephaly subtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the mouse, CDK5RAP2 mutations similar to the human condition result in reduced brain size and a strikingly thin neocortex already at early stages of neurogenesis that persists through adulthood. The microcephaly phenotype in MCPH arises from a neural stem cell proliferation defect. Here, we report a novel role for CDK5RAP2 in the regulation of dendritic development and synaptogenesis of neocortical layer 2/3 pyramidal neurons. CDK5RAP2-deficient murine neurons show poorly branched dendritic arbors and an increased density of immature thin spines and glutamatergic synapses in vivo. Moreover, the excitatory drive is enhanced in ex vivo brain slice preparations of CDK5RAP2 mutant mice. Concurrently, we show that pyramidal neurons receive fewer inhibitory inputs. Together, these findings point towards a shift in the excitation – inhibition balance towards excitation in CDK5RAP2 mutant mice. Thus, MCPH3 is associated not only with a neural progenitor proliferation defect but also with altered function of postmitotic neurons and hence with altered connectivity.
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CDK5RAP2 is required to maintain the germ cell pool during embryonic development
Stem cell reports, 2017Co-Authors: Sami Zaqout, Gisela Stoltenburgdidinger, Paraskevi Bessa, Nadine Kramer, Angela M. KaindlAbstract:Gene products linked to microcephaly have been studied foremost for their role in brain development, while their function in the development of other organs has been largely neglected. Here, we report the critical role of CDK5RAP2 in maintaining the germ cell pool during embryonic development. We highlight that infertility in CDK5RAP2 mutant mice is secondary to a lack of spermatogenic cells in adult mice as a result of an early developmental defect in the germ cells through mitotic delay, prolonged cell cycle, and apoptosis.
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novel alternative splice variants of mouse CDK5RAP2
PLOS ONE, 2015Co-Authors: Nadine Kraemer, Ethiraj Ravindran, Gerda Neubert, Olaf Ninnemann, Lina Issajahns, Shyamala Mani, Angela M. KaindlAbstract:Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by a pronounced reduction of brain volume and intellectual disability. A current model for the microcephaly phenotype invokes a stem cell proliferation and differentiation defect, which has moved the disease into the spotlight of stem cell biology and neurodevelopmental science. Homozygous mutations of the Cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 are one genetic cause of MCPH. To further characterize the pathomechanism underlying MCPH, we generated a conditional CDK5RAP2 LoxP/hCMV Cre mutant mouse. Further analysis, initiated on account of a lack of a microcephaly phenotype in these mutant mice, revealed the presence of previously unknown splice variants of the CDK5RAP2 gene that are at least in part accountable for the lack of microcephaly in the mice.
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loss of CDK5RAP2 affects neural but not non neural mesc differentiation into cardiomyocytes
Cell Cycle, 2015Co-Authors: Nadine Kraemer, Ralph Graf, Sami Zaqout, Ethiraj Ravindran, Gerda Neubert, Detlev Schindler, Olaf Ninnemann, A Seiler, Angela M. KaindlAbstract:Biallelic mutations in the gene encoding centrosomal CDK5RAP2 lead to autosomal recessive primary microcephaly (MCPH), a disorder characterized by pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. The current model for the microcephaly phenotype in MCPH invokes a premature shift from symmetric to asymmetric neural progenitor-cell divisions with a subsequent depletion of the progenitor pool. The isolated neural phenotype, despite the ubiquitous expression of CDK5RAP2, and reports of progressive microcephaly in individual MCPH cases prompted us to investigate neural and non-neural differentiation of CDK5RAP2-depleted and control murine embryonic stem cells (mESC). We demonstrate an accumulating proliferation defect of neurally differentiating CDK5RAP2-depleted mESC and cell death of proliferative and early postmitotic cells. A similar effect does not occur in non-neural differentiation into beating cardiomyocytes, which is in line with the lack of non-central nervous system features in MCPH patients. Our data suggest that MCPH is not only caused by premature differentiation of progenitors, but also by reduced propagation and survival of neural progenitors.
Maryse Lassonde - One of the best experts on this subject based on the ideXlab platform.
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exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum
European Journal of Human Genetics, 2016Co-Authors: Loubna Jouan, Bouchra Ouled Amar Bencheikh, Hussein Daoud, Sylvia Dobrzeniecka, Dan Spiegelman, Daniel Rochefort, Pascale Hince, Anna Szuto, Alexandre Dionnelaporte, Maryse LassondeAbstract:Agenesis of the corpus callosum (ACC) is a common brain malformation which can be observed either as an isolated condition or as part of numerous congenital syndromes. Therefore, cognitive and neurological involvements in patients with ACC are variable, from mild linguistic and behavioral impairments to more severe neurological deficits. To date, the underlying genetic causes of isolated ACC remains elusive and causative genes have yet to be identified. We performed exome sequencing on three acallosal siblings from the same non-consanguineous family and identified compound heterozygous variants, p.[Gly94Arg];[Asn1232Ser], in the protein encoded by the CDK5RAP2 gene, also known as MCPH3, a gene previously reported to cause autosomal recessive primary microcephaly. Our findings suggest a novel role for this gene in the pathogenesis of isolated ACC.
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Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum.
European Journal of Human Genetics, 2015Co-Authors: Loubna Jouan, Bouchra Ouled Amar Bencheikh, Hussein Daoud, Alexandre Dionne-laporte, Sylvia Dobrzeniecka, Dan Spiegelman, Daniel Rochefort, Pascale Hince, Anna Szuto, Maryse LassondeAbstract:Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum
Kelly Arndt - One of the best experts on this subject based on the ideXlab platform.
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compound heterozygote CDK5RAP2 mutations in a guatemalan honduran child with autosomal recessive primary microcephaly failure to thrive and speech delay
American Journal of Medical Genetics Part A, 2015Co-Authors: Mindy H Li, Kelly Arndt, Elliott Mark Weiss, Yaning Wu, Kriti Gwal, Karuna Shekdar, Elaine H ZackaiAbstract:Keywords: autosomal recessive primary microcephaly (MCPH); CDK5RAP2; microcephaly; developmental delay; speech delay; failure to thrive
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Compound heterozygote CDK5RAP2 mutations in a Guatemalan/Honduran child with autosomal recessive primary microcephaly, failure to thrive and speech delay
American Journal of Medical Genetics Part A, 2015Co-Authors: Mindy H Li, Kelly Arndt, Elliott Mark Weiss, Yaning Wu, Kriti Gwal, Karuna Shekdar, Elaine H ZackaiAbstract:Keywords: autosomal recessive primary microcephaly (MCPH); CDK5RAP2; microcephaly; developmental delay; speech delay; failure to thrive
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the first case of CDK5RAP2 related primary microcephaly in a non consanguineous patient identified by next generation sequencing
Brain & Development, 2014Co-Authors: Scott Topper, Catherine Ward Melver, Jennifer Stein, Amanda Reeder, Kelly ArndtAbstract:Abstract Primary autosomal recessive microcephaly (MCPH) is a genetically heterogeneous condition characterized by congenital microcephaly and intellectual disability. To date, 10 MCPH loci have been identified and due to the genetic heterogeneity of this condition, molecular testing for MCPH can be complicated. Our methods involved employing a next generation sequencing panel of MCPH-related genes allowing for the evaluation of multiple disease loci simultaneously. Next generation sequencing analysis of a 6 year old female with primary microcephaly identified novel compound heterozygous mutations (c.524_528del and c.4005-1G>A) in the CDK5RAP2 gene. A review of the published literature to date reveals that only three mutations have been previously reported in the CDK5RAP2 gene in the homozygous state in three Northern Pakistani and one Somali consanguineous MCPH families. Our patient represents the first non-consanguineous Caucasian individual to have been identified with CDK5RAP2 -related MCPH. As only a handful of patients have been reported in the literature with CDK5RAP2 -related MCPH, we anticipate the identification of individuals with CDK5RAP2 mutations from all ethnic backgrounds will continue. Our patient contributes to the ethnic and genotypic spectrum of CDK5RAP2 -related MCPH and supports the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations. Our results also highlight the utility of multi-gene sequencing panels to elucidate the etiology of genetically heterogeneous conditions.
Nadine Kraemer - One of the best experts on this subject based on the ideXlab platform.
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Altered inhibition and excitation in neocortical circuits in congenital microcephaly
Neurobiology of Disease, 2019Co-Authors: Sami Zaqout, Kathrin Blaesius, Yuan-ju Wu, Nadine Kraemer, Lena-luise Becker, Marta Rosário, Christian Rosenmund, Ulf Strauss, Angela M. KaindlAbstract:Abstract Congenital microcephaly is highly associated with intellectual disability. Features of autosomal recessive primary microcephaly subtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the mouse, CDK5RAP2 mutations similar to the human condition result in reduced brain size and a strikingly thin neocortex already at early stages of neurogenesis that persists through adulthood. The microcephaly phenotype in MCPH arises from a neural stem cell proliferation defect. Here, we report a novel role for CDK5RAP2 in the regulation of dendritic development and synaptogenesis of neocortical layer 2/3 pyramidal neurons. CDK5RAP2-deficient murine neurons show poorly branched dendritic arbors and an increased density of immature thin spines and glutamatergic synapses in vivo. Moreover, the excitatory drive is enhanced in ex vivo brain slice preparations of CDK5RAP2 mutant mice. Concurrently, we show that pyramidal neurons receive fewer inhibitory inputs. Together, these findings point towards a shift in the excitation – inhibition balance towards excitation in CDK5RAP2 mutant mice. Thus, MCPH3 is associated not only with a neural progenitor proliferation defect but also with altered function of postmitotic neurons and hence with altered connectivity.
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novel alternative splice variants of mouse CDK5RAP2
PLOS ONE, 2015Co-Authors: Nadine Kraemer, Ethiraj Ravindran, Gerda Neubert, Olaf Ninnemann, Lina Issajahns, Shyamala Mani, Angela M. KaindlAbstract:Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by a pronounced reduction of brain volume and intellectual disability. A current model for the microcephaly phenotype invokes a stem cell proliferation and differentiation defect, which has moved the disease into the spotlight of stem cell biology and neurodevelopmental science. Homozygous mutations of the Cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 are one genetic cause of MCPH. To further characterize the pathomechanism underlying MCPH, we generated a conditional CDK5RAP2 LoxP/hCMV Cre mutant mouse. Further analysis, initiated on account of a lack of a microcephaly phenotype in these mutant mice, revealed the presence of previously unknown splice variants of the CDK5RAP2 gene that are at least in part accountable for the lack of microcephaly in the mice.
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loss of CDK5RAP2 affects neural but not non neural mesc differentiation into cardiomyocytes
Cell Cycle, 2015Co-Authors: Nadine Kraemer, Ralph Graf, Sami Zaqout, Ethiraj Ravindran, Gerda Neubert, Detlev Schindler, Olaf Ninnemann, A Seiler, Angela M. KaindlAbstract:Biallelic mutations in the gene encoding centrosomal CDK5RAP2 lead to autosomal recessive primary microcephaly (MCPH), a disorder characterized by pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. The current model for the microcephaly phenotype in MCPH invokes a premature shift from symmetric to asymmetric neural progenitor-cell divisions with a subsequent depletion of the progenitor pool. The isolated neural phenotype, despite the ubiquitous expression of CDK5RAP2, and reports of progressive microcephaly in individual MCPH cases prompted us to investigate neural and non-neural differentiation of CDK5RAP2-depleted and control murine embryonic stem cells (mESC). We demonstrate an accumulating proliferation defect of neurally differentiating CDK5RAP2-depleted mESC and cell death of proliferative and early postmitotic cells. A similar effect does not occur in non-neural differentiation into beating cardiomyocytes, which is in line with the lack of non-central nervous system features in MCPH patients. Our data suggest that MCPH is not only caused by premature differentiation of progenitors, but also by reduced propagation and survival of neural progenitors.
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clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation
Orphanet Journal of Rare Diseases, 2013Co-Authors: Lina Issa, Nadine Kraemer, Angela M. Kaindl, Olaf Ninnemann, Katrin Mueller, Katja Seufert, Henning Rosenkotter, Michael Buob, Deborah J MorrisrosendahlAbstract:Background Primary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, particularly of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. Despite considerable interest in MCPH as a model disorder for brain development, the underlying pathomechanism has not been definitively established and only four pedigrees with three CDK5RAP2 mutations have been reported. Specifically for MCPH3, no detailed radiological or histological descriptions exist.
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CDK5RAP2 Expression During Murine and Human Brain Development Correlates with Pathology in Primary Autosomal Recessive Microcephaly
Cerebral Cortex, 2012Co-Authors: Lina Issa, Nadine Kraemer, Olaf Ninnemann, Christian H. Rickert, Marco Sifringer, Gisela Stoltenburg-didinger, Angela M. KaindlAbstract:Homozygous mutations in the cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause primary autosomal recessive microcephaly (MCPH). MCPH is characterized by a pronounced reduction of brain volume, particularly of the cerebral cortex, and mental retardation. Though it is a rare developmental disorder, MCPH has moved into the spotlight of neuroscience because of its proposed central role in stem-cell biology and brain development. Investigation of the neural basis of genetically defined MCPH has been limited to animal studies and neuroimaging of affected patients as no neuropathological studies have been published. In the present study, we depict the spatiotemporal expression of CDK5RAP2 in the developing brain of mouse and human. We found intriguing concordance between regions of high CDK5RAP2 expression in the mouse and sites of pathology suggested by neuroimaging studies in humans and mouse. Our findings in human tissue confirm those in mouse tissues, underlining the function of CDK5RAP2 in cell proliferation and arguing for a conserved role of this protein in the development of the mammalian cerebral cortex.
Loubna Jouan - One of the best experts on this subject based on the ideXlab platform.
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exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum
European Journal of Human Genetics, 2016Co-Authors: Loubna Jouan, Bouchra Ouled Amar Bencheikh, Hussein Daoud, Sylvia Dobrzeniecka, Dan Spiegelman, Daniel Rochefort, Pascale Hince, Anna Szuto, Alexandre Dionnelaporte, Maryse LassondeAbstract:Agenesis of the corpus callosum (ACC) is a common brain malformation which can be observed either as an isolated condition or as part of numerous congenital syndromes. Therefore, cognitive and neurological involvements in patients with ACC are variable, from mild linguistic and behavioral impairments to more severe neurological deficits. To date, the underlying genetic causes of isolated ACC remains elusive and causative genes have yet to be identified. We performed exome sequencing on three acallosal siblings from the same non-consanguineous family and identified compound heterozygous variants, p.[Gly94Arg];[Asn1232Ser], in the protein encoded by the CDK5RAP2 gene, also known as MCPH3, a gene previously reported to cause autosomal recessive primary microcephaly. Our findings suggest a novel role for this gene in the pathogenesis of isolated ACC.
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Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum.
European Journal of Human Genetics, 2015Co-Authors: Loubna Jouan, Bouchra Ouled Amar Bencheikh, Hussein Daoud, Alexandre Dionne-laporte, Sylvia Dobrzeniecka, Dan Spiegelman, Daniel Rochefort, Pascale Hince, Anna Szuto, Maryse LassondeAbstract:Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum