[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 08/2015; 10(8):e0136684. DOI:10.1371/journal.pone.0136684 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: How the brain's antioxidant defenses adapt to changing demand is incompletely understood. Here we show that synaptic activity is coupled, via the NMDA receptor (NMDAR), to control of the glutathione antioxidant system. This tunes antioxidant capacity to reflect the elevated needs of an active neuron, guards against future increased demand and maintains redox balance in the brain. This control is mediated via a programme of gene expression changes that boosts the synthesis, recycling and utilization of glutathione, facilitating ROS detoxification and preventing Puma-dependent neuronal apoptosis. Of particular importance to the developing brain is the direct NMDAR-dependent transcriptional control of glutathione biosynthesis, disruption of which can lead to degeneration. Notably, these activity-dependent cell-autonomous mechanisms were found to cooperate with non-cell-autonomous Nrf2-driven support from astrocytes to maintain neuronal GSH levels in the face of oxidative insults. Thus, developmental NMDAR hypofunction and glutathione system deficits, separately implicated in several neurodevelopmental disorders, are mechanistically linked.
[Show abstract][Hide abstract] ABSTRACT: Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.European Journal of Human Genetics advance online publication, 11 March 2015; doi:10.1038/ejhg.2015.26.
European journal of human genetics: EJHG 03/2015; 23(10). DOI:10.1038/ejhg.2015.26 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interstitial deletions of chromosome 12p are rare, and the phenotype spectrum is therefore still unknown. The thirteen patients reported so far suffer from developmental delay, optic nerve hypoplasia, micropenis, hypoplastic hair and skin, oligodontia, brachydactyly, and arterial hypertension. We report a de novo 12p12.2–p11.22 deletion of 9.2 Mb detected by array CGH analysis in a boy with global developmental delay, muscular hypotonia, postnatal microcephaly, facial dysmorphism including small ears, epicanthus, broad nasal bridge and hypoplastic nostrils. In addition, the patient had optic nerve atrophy, inverted nipples, micropenis, and a hemangioma. The deleted region encompasses more than 40 reference genes. We compare phenotype and deletion extent of our index patient to that of previous reports and thereby contribute to the understanding of interstitial 12p deletion phenotypes. Knowledge of the pattern of this deletion phenotype will help clinicians to diagnose this abnormality in their patients and to counsel the parents accordingly. Further descriptions may be able to contribute to the clarification.
Meta Gene 12/2014; 2(1):72–82. DOI:10.1016/j.mgene.2013.10.014
[Show abstract][Hide abstract] ABSTRACT: To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD).
We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts.
In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts.
We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.
[Show abstract][Hide abstract] ABSTRACT: The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0116-6) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: Warburg micro syndrome (WARBM) is a genetic heterogeneous disease characterized by microcephaly, intellectual disability, brain, ocular, and endocrine anomalies. WARBM1-4 can be caused by biallelic mutations of the RAB3GAP1 (RAB3 GTPase-activating protein 1), RAB3GAP2, RAB18 (RAS-associated protein RAB18), or TBC1D20 (TBC1 domain protein, member 20) gene, respectively. Here, we delineate the so far largest intragenic homozygous RAB3GAP1 microdeletion. Despite the size of the RAB3GAP1 gene deletion, the patient phenotype is mainly consistent with that of other WARBM1 patients, supporting strongly the theory that WARBM1 is caused by a loss of RAB3GAP1 function. We further highlight osteopenia as a feature of WARBM1.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0113-9) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: Autosomal recessive primary microcephaly (MCPH) is a genetically heterogeneous disease characterized by a pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. Here, we summarize the genetic causes of MCPH types 1-12 known to date.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 04/2014; 18(4). DOI:10.1016/j.ejpn.2014.03.010 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess the diagnostic approach to microcephaly in childhood and to identify the prevalence of the various underlying causes/disease entities.
We conducted a retrospective study on a cohort of 680 children with microcephaly (399 males, 281 females; mean age at presentation 7-8mo, range 1mo-5y) from patients presenting to Charité - University Medicine Berlin (n=474) and University Hospital Dresden (n=206). Patient discharge letters were searched electronically to identify cases of microcephaly, and then the medical records of these patients were used to analyze parameters for distribution.
The putative aetiology for microcephaly was ascertained in 59% of all patients, leaving 41% without a definite diagnosis. In the cohort of pathogenetically defined microcephaly, genetic causes were identified in about half of the patients, perinatal brain damage accounted for 45%, and postnatal brain damage for 3% of the cases. Microcephaly was associated with intellectual impairment in 65% of participants, epilepsy was diagnosed in 43%, and ophthalmological disorders were found in 30%. Brain magnetic resonance imaging revealed abnormalities in 76% of participants.
Microcephaly remains a poorly defined condition, and a uniform diagnostic approach is urgently needed. A definite aetiological diagnosis is important in order to predict the prognosis and offer genetic counselling. Identifying gene mutations as causes of microcephaly increases our knowledge of brain development and the clinical spectrum of microcephaly. We therefore propose a standardized initial diagnostic approach to microcephaly.
[Show abstract][Hide abstract] ABSTRACT: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified.Methods/results: We characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c.1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient's immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent.
We propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.
[Show abstract][Hide abstract] ABSTRACT: Duchenne muscular dystrophy (DMD) is one of the most common hereditary degenerative neuromuscular diseases and caused by mutations in the dystrophin gene. The objective of the retrospective study was to describe growth and psychomotor development of patients with DMD and to detect a possible genotype-phenotype correlation. Data from 263 patients with DMD (mean age 7.1 years) treated at the Departments of Pediatric Neurology in three German University Hospitals was assessed with respect to body measurements (length, weight, body mass index BMI, head circumference OFC), motor and cognitive development as well as genotype (site of mutation). Anthropometric measures and developmental data were compared to those of a reference population and deviations were analyzed for their frequency in the cohort as well as in relation to the genotypes. Corticosteroid therapy was implemented in 29 from 263 patients. Overall 30% of the patients exhibit a short statue (length < 3rd centile) with onset early in development at 2-5 years of age, and this is even more prevalent when steroid therapy is applied (45% of patients with steroid therapy). The BMI shows a rightwards shift (68% > 50th centile) and the OFC a leftwards shift (65% < 50th centile, 5% microcephaly). Gross motor development is delayed in a third of the patients (mean age at walking 18.3 months, 30% > 18 months, 8% > 24 months). Almost half of the patients show cognitive impairment (26% learning disability, 17% intellectual disability). Although there is no strict genotype-phenotype correlation, particularly mutations in the distal part of the dystrophin gene are frequently associated with short stature and a high rate of microcephaly as well as cognitive impairment.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 09/2013; 18(1). DOI:10.1016/j.ejpn.2013.08.008 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: •47,XYY syndrome is a frequent sex chromosome aneuploidy.•Overview of characteristic symptoms of 47,XXY•First report of 47,XYY and microcephaly in a preterm child•Brief differential diagnosis of microcephaly
[Show abstract][Hide abstract] ABSTRACT: The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.
We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)−1β–induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation.
We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein–coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization.
Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders. Ann Neurol 2013;73:667–678
Annals of Neurology 05/2013; 73(5). DOI:10.1002/ana.23868 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: True microcephaly (head circumference ≤-3SD), either primary (present at birth) or secondary (of postnatal onset) results from an imbalance between progenitor cell production and cell death that lead to a reduced number of neuronal and glial cells within the brain, resulting in reduced brain growth. Primary non-syndromal microcephalies are recessive disorders resulting from abnormal control of mitotic spindle and cell cycle kinetics in progenitor cells. Microcephaly is also a frequent sign of defects in DNA double- and/or single-strand break repair and in nucleotide excision repair, in which it often is associated with general growth impairment. In these etiologies, cognitive functions are reasonably well preserved despite severe reduction in brain volume. Neuronal migration defects are often associated with secondary microcephaly, as are anomalies of telencephalic cleavage. Secondary microcephalies are often associated with increased neuronal death, and can be associated with metabolic disorders such as serine deficiency or thiamine pyrophosphate transporter deficiency. Microcephaly can be associated with hundreds of syndromal congenital anomalies, including many chromosomal disorders. Genetic etiologies of developmental microcephalies are reviewed.
Handbook of Clinical Neurology 04/2013; 111:129-41. DOI:10.1016/B978-0-444-52891-9.00013-0