We report a case of irritable bowel syndrome (IBS), diarrhea subtype, characterized by daily ‘morning rush’ and episodic acute exacerbations brought on by common IBS trigger foods including insoluble ...fiber, red wine and large/rich meals. The patient also had a history of migraine headaches, and a family history suggesting a common diathesis for both disorders. Given hypothesized contributions to IBS from dysregulation of the enteric serotonergic system, a trial of low-dose triptan medication was implemented in the context of the patient’s known IBS triggers, with highly satisfactory results.
Dopa-responsive dystonia is a hereditary disease characterized by inadequate dopamine production. Autosomal-dominant cases result from mutations in the GCH1 gene, encoding guanosine triphosphate ...(GTP)-cyclohydrolase 1. The most common presenting manifestation is dystonia of a lower extremity, often worsening late in the day. The onset and clinical severity are variable, sometimes even within a single family. Gender effects on allele penetrance have been reported. We present a male toddler with dopa-responsive dystonia caused by an autosomal-dominant GCH1 mutation. Three other family members were also found to carry the mutation, with widely different functional consequences.
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, ...and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations corrected.Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.
Congenital absence of the midbrain and upper pons is a rare human malformation. We describe two unrelated infants with this anomaly and cerebellar hypoplasia who were born at term but died in early ...infancy from lack of central respiratory drive. MRI in both cases disclosed the lesions during life. Neuropathological examination, performed in one, included immunocytochemical studies of NeuN, synaptophysin, vimentin, and glial fibrillary acidic protein (GFAP). Autopsy revealed a thin midline cord passing through the clivus, in place of the midbrain; it corresponded to hypoplastic and fused corticospinal tracts with ectopic neural tissue in the surrounding leptomeninges. Some ectopia were immunoreactive for synaptophysin and NeuN and others were nonreactive. The neural surfaces facing the subarachnoid fluid-filled space left by the absent midbrain and upper pons were lined by an abnormal villous ependyma. The architecture of the cerebellar cortex was imperfect but generally normal, and Bergmann glial cells had normal radial processes shown by vimentin and GFAP. Structures of the telencephalon, diencephalon, lower brainstem, and spinal cord were generally well formed, but inferior olivary and dentate nuclei were rudimentary and the spinal central canal was dilated at lumbar levels. The cerebral cortex was normally laminated, but pyramidal neurons of layer 5 were sparse in the frontal lobes. The hippocampus, olfactory system, and corpus callosum were formed. An ectopic lingual thyroid was found and had been associated with hypothyroidism during life. A murine model resembling this dysgenesis is demonstrated by homozygous mutations of the organizer genes Wnt1 or En1, also resulting in cerebellar aplasia, and En2, associated with cerebellar hypoplasia. These genes are essential to the formation of the mesencephalic neuromere and rhombomere 1 (metencephalon or upper pons and cerebellum). Pax8 has binding sites in the promoter for En2 and is essential for thyroid development. We speculate that in the human, the failure to form a mesencephalon and metencephalon, with cerebellar hypoplasia, results from a mutation or deletion in the EN2 (Engrailed-2) gene.
Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and ...constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, Tbr1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3β inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD.
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•Tbr1 promotes and maintains spine maturation and synaptogenesis through WNT signaling•Promoting WNT signaling rescues dendritic spine and synaptic defects in Tbr1 mutants•TBR1 directly regulates transcriptional circuits that control ASD-risk genes
Fazel Darbandi et al. demonstrate that TBR1 directly regulates transcriptional circuits in cortical layers 5 and 6, which promote dendritic spine and synaptic density. Enhancing WNT signaling rescues dendritic spine maturation and synaptogenesis defects in Tbr1 mutants. These results provide insights into mechanisms that underlie ASD pathophysiology.
Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during ...vertebrate development. Dishevelled (Dsh/Dvl) is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins.
We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure.
These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene expression and cell movements that are essential for gastrulation.
Background Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements ...during vertebrate development. Dishevelled (Dsh/Dvl) is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins. Methodology We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure. Conclusions These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene expression and cell movements that are essential for gastrulation.
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