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Nature May 2017The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from...
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
Topics: Autistic Disorder; Cell Line; Cell Movement; Cells, Cultured; Female; GABAergic Neurons; Glutamic Acid; Humans; Interneurons; Long QT Syndrome; Male; Models, Biological; Neurogenesis; Neurons; Pluripotent Stem Cells; Prosencephalon; Spheroids, Cellular; Synapses; Syndactyly
PubMed: 28445465
DOI: 10.1038/nature22330 -
Genetics in Medicine : Official Journal... Oct 2021CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously...
PURPOSE
CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.
METHODS
We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.
RESULTS
Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.
CONCLUSION
We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
Topics: Autistic Disorder; Calcium Channels, L-Type; Humans; Long QT Syndrome; Phenotype; Syndactyly
PubMed: 34163037
DOI: 10.1038/s41436-021-01232-8 -
Cell May 2020Expansions of amino acid repeats occur in >20 inherited human disorders, and many occur in intrinsically disordered regions (IDRs) of transcription factors (TFs). Such...
Expansions of amino acid repeats occur in >20 inherited human disorders, and many occur in intrinsically disordered regions (IDRs) of transcription factors (TFs). Such diseases are associated with protein aggregation, but the contribution of aggregates to pathology has been controversial. Here, we report that alanine repeat expansions in the HOXD13 TF, which cause hereditary synpolydactyly in humans, alter its phase separation capacity and its capacity to co-condense with transcriptional co-activators. HOXD13 repeat expansions perturb the composition of HOXD13-containing condensates in vitro and in vivo and alter the transcriptional program in a cell-specific manner in a mouse model of synpolydactyly. Disease-associated repeat expansions in other TFs (HOXA13, RUNX2, and TBP) were similarly found to alter their phase separation. These results suggest that unblending of transcriptional condensates may underlie human pathologies. We present a molecular classification of TF IDRs, which provides a framework to dissect TF function in diseases associated with transcriptional dysregulation.
Topics: Alanine; Animals; Base Sequence; DNA Repeat Expansion; Disease Models, Animal; Homeodomain Proteins; Humans; Male; Mice; Mutation; Pedigree; Syndactyly; Transcription Factors
PubMed: 32386547
DOI: 10.1016/j.cell.2020.04.018 -
Cell Stem Cell Feb 2022Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration...
Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Ca1.2. Here, we find that acute pharmacological modulation of Ca1.2 can regulate the saltation length, but not the frequency, of interneuron migration in TS. Interestingly, the defect in saltation length is related to aberrant actomyosin and myosin light chain (MLC) phosphorylation, while the defect in saltation frequency is driven by enhanced γ-aminobutyric acid (GABA) sensitivity and can be restored by GABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activity in TS that is exacerbated by interneuron migration. Taken together, these studies reveal a complex role of LTCC function in human cortical interneuron migration and strategies to restore deficits in the context of disease.
Topics: Autistic Disorder; Cell Movement; Cerebral Cortex; Humans; Interneurons; Long QT Syndrome; Prosencephalon; Syndactyly
PubMed: 34990580
DOI: 10.1016/j.stem.2021.11.011 -
Annual Review of Physiology Feb 2021The identification of a gain-of-function mutation in as the cause of Timothy syndrome, a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted... (Review)
Review
The identification of a gain-of-function mutation in as the cause of Timothy syndrome, a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted roles for the L-type voltage-gated Ca channel Ca1.2 in nonexcitable cells. Previous studies in cells and animal models had suggested that several voltage-gated Ca channels (VGCCs) regulated critical signaling events in various cell types that are not expected to support action potentials, but definitive data were lacking. VGCCs occupy a special position among ion channels, uniquely able to translate membrane excitability into the cytoplasmic Ca changes that underlie the cellular responses to electrical activity. Yet how these channels function in cells not firing action potentials and what the consequences of their actions are in nonexcitable cells remain critical questions. The development of new animal and cellular models and the emergence of large data sets and unbiased genome screens have added to our understanding of the unanticipated roles for VGCCs in nonexcitable cells. Here, we review current knowledge of VGCC regulation and function in nonexcitable tissues and cells, with the goal of providing a platform for continued investigation.
Topics: Action Potentials; Animals; Autistic Disorder; Calcium; Calcium Channels; Calcium Signaling; Humans; Long QT Syndrome; Signal Transduction; Syndactyly
PubMed: 33106102
DOI: 10.1146/annurev-physiol-031620-091043 -
Orphanet Journal of Rare Diseases May 2022The formation of the digits is a tightly regulated process. During embryogenesis, disturbance of genetic pathways in limb development could result in syndactyly; a... (Review)
Review
The formation of the digits is a tightly regulated process. During embryogenesis, disturbance of genetic pathways in limb development could result in syndactyly; a common congenital malformation consisting of webbing in adjacent digits. Currently, there is a paucity of knowledge regarding the exact developmental mechanism leading to this condition. The best studied canonical interactions of Wingless-type-Bone Morphogenic Protein-Fibroblast Growth Factor (WNT-BMP-FGF8), plays a role in the interdigital cell death (ICD) which is thought to be repressed in human syndactyly. Animal studies have displayed other pathways such as the Notch signaling, metalloprotease and non-canonical WNT-Planar cell polarity (PCP), to also contribute to failure of ICD, although less prominence has been given. The current diagnosis is based on a clinical evaluation followed by radiography when indicated, and surgical release of digits at 6 months of age is recommended. This review discusses the interactions repressing ICD in syndactyly, and characterizes genes associated with non-syndromic and selected syndromes involving syndactyly, according to the best studied canonical WNT-BMP-FGF interactions in humans. Additionally, the controversies regarding the current syndactyly classification and the effect of non-coding elements are evaluated, which to our knowledge has not been previously highlighted. The aim of the review is to better understand the developmental process leading to this condition.
Topics: Animals; Extremities; Fibroblast Growth Factors; Humans; Signal Transduction; Syndactyly
PubMed: 35549993
DOI: 10.1186/s13023-022-02339-0 -
European Journal of Human Genetics :... Aug 2012Syndactyly is one of the most common hereditary limb malformations depicting the fusion of certain fingers and/or toes. It may occur as an isolated entity or a component... (Review)
Review
Syndactyly is one of the most common hereditary limb malformations depicting the fusion of certain fingers and/or toes. It may occur as an isolated entity or a component of more than 300 syndromic anomalies. Syndactylies exhibit great inter- and intra-familial clinical variability. Even within a subject, phenotype can be unilateral or bilateral and symmetrical or asymmetrical. At least nine non-syndromic syndactylies with additional sub-types have been characterized. Most of the syndactyly types are inherited as autosomal dominant but two autosomal recessive and an X-linked recessive entity have also been described. Whereas the underlying genes/mutations for types II-1, III, IV, V, and VII have been worked out, the etiology and molecular basis of the other syndactyly types remain unknown. In this communication, based on an overview of well-characterized isolated syndactylies, their cardinal phenotypes, inheritance patterns, and clinical and genetic heterogeneities, a 'current classification scheme' is presented. Despite considerable progress in the understanding of syndactyly at clinical and molecular levels, fundamental questions regarding the disturbed developmental mechanisms leading to fused digits, remain to be answered.
Topics: Humans; Phenotype; Syndactyly
PubMed: 22333904
DOI: 10.1038/ejhg.2012.14 -
Indian Journal of Ophthalmology Mar 2016Oculodentodigital dysplasia is a rare, autosomal dominant disorder with high penetrance and variable expressivity, caused by mutations in the connexin 43 or gap junction...
Oculodentodigital dysplasia is a rare, autosomal dominant disorder with high penetrance and variable expressivity, caused by mutations in the connexin 43 or gap junction protein alpha-1 gene. It has been diagnosed in fewer than 300 people worldwide with an incidence of around 1 in 10 million. It affects many parts of the body, particularly eyes (oculo), teeth (dento), and fingers and/or toes (digital). The common clinical features include facial dysmorphism with thin nose, microphthalmia, syndactyly, tooth anomalies such as enamel hypoplasia, anodontia, microdontia, early tooth loss and conductive deafness. Other less common features are abnormalities of the skin and its appendages, such as brittle nails, sparse hair, and neurological abnormalities. To prevent this syndrome from being overlooked, awareness of possible symptoms is necessary. Early recognition can prevent blindness, dental problems and learning disabilities. Described here is the case of a 21-year-old male who presented to the ophthalmology outpatient department with a complaint of bilateral progressive loss of vision since childhood.
Topics: Abnormalities, Multiple; Craniofacial Abnormalities; Eye Abnormalities; Foot Deformities, Congenital; Humans; Male; Microphthalmos; Syndactyly; Tooth Abnormalities; Vision, Low; Visual Acuity; Young Adult
PubMed: 27146935
DOI: 10.4103/0301-4738.180191 -
Orphanet Journal of Rare Diseases Jun 2006Pfeiffer syndrome is a rare autosomal dominantly inherited disorder that associates craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly on... (Review)
Review
Pfeiffer syndrome is a rare autosomal dominantly inherited disorder that associates craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly on hands and feet. Hydrocephaly may be found occasionally, along with severe ocular proptosis, ankylosed elbows, abnormal viscera, and slow development. Based on the severity of the phenotype, Pfeiffer syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay and neurological complications. Type 3 is similar to type 2 but without a cloverleaf skull. Clinical overlap between the three types may occur. Pfeiffer syndrome affects about 1 in 100,000 individuals. The disorder can be caused by mutations in the fibroblast growth factor receptor genes FGFR-1 or FGFR-2. Pfeiffer syndrome can be diagnosed prenatally by sonography showing craniosynostosis, hypertelorism with proptosis, and broad thumb, or molecularly if it concerns a recurrence and the causative mutation was found. Molecular genetic testing is important to confirm the diagnosis. Management includes multiple-staged surgery of craniosynostosis. Midfacial surgery is performed to reduce the exophthalmos and the midfacial hypoplasia.
Topics: Acrocephalosyndactylia; Fingers; Genes, Dominant; Humans; Mutation; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 2; Toes
PubMed: 16740155
DOI: 10.1186/1750-1172-1-19 -
Clinical Genetics Jan 2019Split-hand/foot malformation (SHFM) is caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9. The clinical features of SHFM caused by mutations of... (Review)
Review
Split-hand/foot malformation (SHFM) is caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9. The clinical features of SHFM caused by mutations of these genes are not distinguishable. This implies that in normal situations these SHFM-associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet. The mutations in SHFM-related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM. Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf-Bmp-Msx signaling on apoptotic cell death. Loss of digit identity in SHFM is hypothesized to be the effects of misexpression of HOX genes, abnormal SHH gradient, or the loss of balance between GLI3A and GLI3R. Disruption of canonical and non-canonical Wnt signaling is involved in the pathogenesis of SHFM. Whatever the causative genes of SHFM are, the mutations seem to lead to dysregulation of Fgf8 in AER cells of the central parts of the hands and feet and disruption of Wnt-Bmp-Fgf signaling pathways in AER.
Topics: Bone Morphogenetic Proteins; Fibroblast Growth Factor 8; Foot Deformities, Congenital; Gene Expression Regulation; Hand Deformities, Congenital; Homeodomain Proteins; Humans; Limb Deformities, Congenital; Mutation; Syndactyly; Wnt Signaling Pathway
PubMed: 30101460
DOI: 10.1111/cge.13434