Distal arthrogryposis with variable clinical expression caused by TNNI2 mutation

Distal arthrogryposis (DA) is a clinically and genetically heterogeneous disorder with multiple joint contractures. We describe a female DA patient with hand and foot deformities, and right-sided torticollis. Using exome sequencing, we identified a novel TNNI2 mutation (c.485>A, p.Arg162Lys) in the patient and her father. The father has no typical DA but hip dysplasia. This may explain the clinical features of DA2B in this family, but with variable clinical expression

Clinical Outcomes of Cetuximab and Paclitaxel after Progression on Immune Checkpoint Inhibitors in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Background and Objectives: In recent years, the effectiveness of chemotherapy after immune checkpoint inhibitor administration has attracted attention in various cancers, including head and neck cancers. However, individual assessments of the administered chemotherapy regimens are insufficient. This study aimed to evaluate the efficacy and safety of chemotherapy after immune checkpoint inhibitor administration in recurrent metastatic head and neck cancer by focusing on a single regimen. Materials and Methods: We retrospectively reviewed clinical and radiological data from the medical records of 18 patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who received systemic chemotherapy with weekly cetuximab and paclitaxel (Cmab + PTX) after progression following immune checkpoint inhibitor (ICI) therapy. The objective response rate (ORR) and disease control rate (DCR) were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: In all patients, the ORR, DCR, median PFS, and median OS were 44.4%, 72.2%, 3.8 months, and 9.6 months, respectively. Regarding AEs, three patients developed grade 3 neutropenia. Grade 3 anemia, paronychia, asthenia, and peripheral neuropathy were observed in one patient each. There were no treatment-related deaths. Conclusions: Cmab + PTX was shown to maintain high efficacy and acceptable safety for R/M HNSCC that progressed after ICI therapy. Further research is needed to establish optimal treatment sequences and drug combinations for recurrent R/M HNSCC

Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A(1) activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.ArticleSCIENTIFIC REPORTS. 4:7132 (2014)journal articl

De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy

Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements

Molecular mechanisms of cooperative binding of transcription factors Runx1–CBFβ–Ets1 on the TCRα gene enhancer

<div><p>Ets1 is an essential transcription factor (TF) for several important physiological processes, including cell proliferation and differentiation. Its recognition of the enhancer region of the <i>TCRα</i> gene is enhanced by the cooperative binding of the Runx1–CBFβ heterodimer, with the cancelation of phosphorylation-dependent autoinhibition. The detailed mechanism of this interesting cooperativity between Ets1 and the Runx1–CBFβ heterodimer is still largely unclear. Here, we investigated the molecular mechanisms of this cooperativity, by using molecular dynamics simulations. Consequently, we detected high flexibility of the loop region between the HI2 and H1 helices of Ets1. Upon Runx1–CBFβ heterodimer binding, this loop transiently adopts various sub-stable conformations in its interactions with the DNA. In addition, a network analysis suggested an allosteric pathway in the molecular assembly and identified some key residues that coincide with previous experimental studies. Our simulations suggest that the cooperative binding of Ets1 and the Runx1–CBFβ heterodimer alters the DNA conformation and induces sub-stable conformations of the HI2–H1 loop of Ets1. This phenomenon increases the flexibility of the regulatory module, including the HI2 helix, and destabilizes the inhibitory form of this module. Thus, we hypothesize that this effect facilitates Ets1–DNA binding and prevents the phosphorylation-dependent DNA binding autoinhibition.</p></div