Two novel variants in signal transduction and activator of transcription 1 (STAT1) coiled-coil region cause STAT1 gain of function in an infant presenting with Pneumocystis jiroveci pneumonia (PJP) and CMV viremia

Abstract MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA). Patients present congenital macrothrombocytopenia and inclusions of NMMHC-IIA in leukocytes, and have a variable risk of developing kidney damage, sensorineural deafness, presenile cataracts and/or liver enzymes abnormalities. The spectrum of mutations found in MYH9-RD patients is limited and the incidence and severity of the non-congenital features are predicted by the causative MYH9 variant. In particular, different alterations of the C-terminal tail domain of NMMHC-IIA associate with remarkably different disease evolution. We report four novel MYH9 mutations affecting the tail domain of NMMHC-IIA and responsible for MYH9-RD in four families. Two variants cause amino acid substitutions in the coiled-coil region of NMMHC-IIA, while the other two are a splicing variant and a single nucleotide deletion both resulting in frameshift alterations of the short non-helical tailpiece. Characterization of phenotypes of affected individuals shows that all of these novel variants are associated with a mild clinical evolution of the disease.

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Faculty Opinions recommendation of A gain-of-function mutation in a plant disease resistance gene leads to constitutive activation of downstream signal transduction pathways in suppressor of npr1-1, constitutive 1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016258.200354 ◽

2003 ◽

Author(s):

Laurence Rahme

Keyword(s):

Signal Transduction ◽

Disease Resistance ◽

Resistance Gene ◽

Plant Disease Resistance ◽

Plant Disease ◽

Signal Transduction Pathways ◽

Disease Resistance Gene ◽

Gain Of Function ◽

Constitutive Activation ◽

Plant Disease Resistance Gene

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Optimal timing for discontinuation of Pneumocystis jiroveci pneumonia prophylaxis in adult patients on highly active antiretroviral therapy (HAART) for HIV infection

10.1002/14651858.cd009556 ◽

2012 ◽

Author(s):

Elizabeth Mbabazi ◽

Olalekan A Uthman ◽

Taryn Young

Keyword(s):

Antiretroviral Therapy ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

Adult Patients ◽

Optimal Timing ◽

Pneumocystis Jiroveci ◽

Pneumocystis Jiroveci Pneumonia ◽

Highly Active

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Mapping of a Yeast G Protein βγ Signaling Interaction

Genetics ◽

10.1093/genetics/150.4.1407 ◽

1998 ◽

Vol 150 (4) ◽

pp. 1407-1417 ◽

Cited By ~ 1

Author(s):

Simon J Dowell ◽

Anne L Bishop ◽

Susan L Dyos ◽

Andrew J Brown ◽

Malcolm S Whiteway

Keyword(s):

Signal Transduction ◽

Map Kinase ◽

G Protein ◽

Coiled Coil ◽

Receptor Activation ◽

Temperature Sensitive ◽

Hydrophobic Residues ◽

Map Kinase Cascade ◽

Kinase Cascade

Abstract The mating pathway of Saccharomyces cerevisiae is widely used as a model system for G protein-coupled receptor-mediated signal transduction. Following receptor activation by the binding of mating pheromones, G protein βγ subunits transmit the signal to a MAP kinase cascade, which involves interaction of Gβ (Ste4p) with the MAP kinase scaffold protein Ste5p. Here, we identify residues in Ste4p required for the interaction with Ste5p. These residues define a new signaling interface close to the Ste20p binding site within the Gβγ coiled-coil. Ste4p mutants defective in the Ste5p interaction interact efficiently with Gpa1p (Gα) and Ste18p (Gγ) but cannot function in signal transduction because cells expressing these mutants are sterile. Ste4 L65S is temperature-sensitive for its interaction with Ste5p, and also for signaling. We have identified a Ste5p mutant (L196A) that displays a synthetic interaction defect with Ste4 L65S, providing strong evidence that Ste4p and Ste5p interact directly in vivo through an interface that involves hydrophobic residues. The correlation between disruption of the Ste4p-Ste5p interaction and sterility confirms the importance of this interaction in signal transduction. Identification of the Gβγ coiled-coil in Ste5p binding may set a precedent for Gβγ-effector interactions in more complex organisms.

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A Coiled-Coil Domain of Melanophilin Is Essential for Myosin Va Recruitment and Melanosome Transport in Melanocytes

Molecular Biology of the Cell ◽

10.1091/mbc.e06-05-0457 ◽

2006 ◽

Vol 17 (11) ◽

pp. 4720-4735 ◽

Cited By ~ 61

Author(s):

Alistair N. Hume ◽

Abul K. Tarafder ◽

José S. Ramalho ◽

Elena V. Sviderskaya ◽

Miguel C. Seabra

Keyword(s):

Coiled Coil ◽

Binding Domain ◽

Actin Binding ◽

Binding Studies ◽

Null Cell ◽

Coiled Coil Region ◽

Actin Binding Domain ◽

Transport Assay ◽

Myosin Va

Melanophilin (Mlph) regulates retention of melanosomes at the peripheral actin cytoskeleton of melanocytes, a process essential for normal mammalian pigmentation. Mlph is proposed to be a modular protein binding the melanosome-associated protein Rab27a, Myosin Va (MyoVa), actin, and microtubule end-binding protein (EB1), via distinct N-terminal Rab27a-binding domain (R27BD), medial MyoVa-binding domain (MBD), and C-terminal actin-binding domain (ABD), respectively. We developed a novel melanosome transport assay using a Mlph-null cell line to study formation of the active Rab27a:Mlph:MyoVa complex. Recruitment of MyoVa to melanosomes correlated with rescue of melanosome transport and required intact R27BD together with MBD exon F–binding region (EFBD) and unexpectedly a potential coiled-coil forming sequence within ABD. In vitro binding studies indicate that the coiled-coil region enhances binding of MyoVa by Mlph MBD. Other regions of Mlph reported to interact with MyoVa globular tail, actin, or EB1 are not essential for melanosome transport rescue. The strict correlation between melanosomal MyoVa recruitment and rescue of melanosome distribution suggests that stable interaction with Mlph and MyoVa activation are nondissociable events. Our results highlight the importance of the coiled-coil region together with R27BD and EFBD regions of Mlph in the formation of the active melanosomal Rab27a-Mlph-MyoVa complex.

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