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Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury.
METHODS - To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines.
RESULTS - In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells.
CONCLUSIONS - These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.
Copyright © 2019 by the American Society of Nephrology.
BACKGROUND - Mutations in SLC6A1 have been associated mainly with myoclonic atonic epilepsy (MAE) and intellectual disability. We identified a novel missense mutation in a patient with Lennox-Gastaut syndrome (LGS) characterized by severe seizures and developmental delay.
METHODS - Exome Sequencing was performed in an epilepsy patient cohort. The impact of the mutation was evaluated by H γ-aminobutyric acid (GABA) uptake, structural modeling, live cell microscopy, cell surface biotinylation and a high-throughput assay flow cytometry in both neurons and non neuronal cells.
RESULTS - We discovered a heterozygous missense mutation (c700G to A [pG234S) in the SLC6A1 encoding GABA transporter 1 (GAT-1). Structural modeling suggests the mutation destabilizes the global protein conformation. With transient expression of enhanced yellow fluorescence protein (YFP) tagged rat GAT-1 cDNAs, we demonstrated that the mutant GAT-1(G234S) transporter had reduced total protein expression in both rat cortical neurons and HEK 293 T cells. With a high-throughput flow cytometry assay and live cell surface biotinylation, we demonstrated that the mutant GAT-1(G234S) had reduced cell surface expression. H radioactive labeling GABA uptake assay in HeLa cells indicated a reduced function of the mutant GAT-1(G234S).
CONCLUSIONS - This mutation caused instability of the mutant transporter protein, which resulted in reduced cell surface and total protein levels. The mutation also caused reduced GABA uptake in addition to reduced protein expression, leading to reduced GABA clearance, and altered GABAergic signaling in the brain. The impaired trafficking and reduced GABA uptake function may explain the epilepsy phenotype in the patient.
Copyright © 2019. Published by Elsevier Inc.
A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant atrial natriuretic peptide (Mut-ANP), has been linked with familial atrial fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na (NaV1.5) and Ca (CaV1.2/CaV1.3) channel expression and currents (I, I) and action potential durations (APD/APD/APD) were significantly reduced in H-fsMut-NPPA mice while the rectifier K channel current (I) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na, Ca and K channels creating an electrophysiologic substrate for reentrant AF.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Allosteric regulation of methylmalonyl-CoA mutase (MCM) by the G-protein chaperone CblA is transduced via three "switch" elements that gate the movement of the B cofactor to and from MCM. Mutations in CblA and MCM cause hereditary methylmalonic aciduria. Unlike the bacterial orthologs used previously to model disease-causing mutations, human MCM and CblA exhibit a complex pattern of regulation that involves interconverting oligomers, which are differentially sensitive to the presence of GTP versus GDP. Patient mutations in the switch III region of CblA perturb the nucleotide-sensitive distribution of the oligomeric complexes with MCM, leading to loss of regulated movement of B to and/or from MCM and explain the molecular mechanism of the resulting disease.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Lyn kinase (Lck/Yes related novel protein tyrosine kinase) belongs to the family of Src-related non-receptor tyrosine kinases. Consistent with physiological roles in cell growth and proliferation, aberrant function of Lyn is associated with various forms of cancer, including leukemia, breast cancer and melanoma. Here, we determine a 1.3 Å resolution crystal structure of the polyproline-binding SH3 regulatory domain of human Lyn kinase, which adopts a five-stranded β-barrel fold. Mapping of cancer-associated point mutations onto this structure reveals that these amino acid substitutions are distributed throughout the SH3 domain and may affect Lyn kinase function distinctly.
The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using CIBERSORT, TIMER and TIDE deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage (T3/T4, odds ratio (OR) = 2.6, CI = 1.4-4.5, P = 5.4 × 10-4). Increased dendritic cells (OR = 3.4, CI = 1.9-6.3, P = 5.5 × 10-5) and neutrophils (OR = 10.5, CI = 2.7-44, P = 8.7 × 10-4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR = 4.5, CI = 1.6-13, P = 4.9 × 10-3) and neutrophils negatively correlate with follicular morphology (OR = 1.3 × 10-3, CI = 5.3 × 10-5-0.031, P = 4.1 × 10-5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using three computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.
OBJECTIVE - Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown.
METHODS - In this study, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1, PDX1 mutations and engineered isogenic cell lines carrying homozygous PDX1, PDX1 mutations and a heterozygous PDX1 loss-of-function mutation (PDX1).
RESULTS - Using an in vitro β-cell differentiation protocol, we demonstrated that both, heterozygous PDX1, PDX1 and homozygous PDX1, PDX1 mutations impair β-cell differentiation and function. Furthermore, PDX1 and PDX1 mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1 and PDX1 mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT, both involved in insulin synthesis and secretion.
CONCLUSIONS - Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function and contribute to the predisposition for diabetes.
Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MeCP2) gene. This Science & Society article focuses on pharmacological strategies that attack RTT treatment from multiple angles, including drug repurposing and de novo discovery efforts, and discusses the impacts of preclinical study design and translationally relevant outcome measures.
Copyright © 2019 Elsevier Ltd. All rights reserved.