Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis Anna C. Thomas,

Slides:

Advertisements

Similar presentations

From: IGF-1 Regulates the Extracellular Level of Active MMP-2 and Promotes Müller Glial Cell Motility Invest. Ophthalmol. Vis. Sci ;56(11):

Advertisements

Interaction between G Protein-Coupled Receptor 143 and Tyrosinase: Implications for Understanding Ocular Albinism Type 1 Elisabetta De Filippo, Anke.

Wei Liu, Kun Ma, Sun Hyung Kwon, Ravi Garg, Yoda R

Maik Dahlhoff, Sukalp Muzumdar, Matthias Schäfer, Marlon R. Schneider

A Modeling Conundrum: Murine Models for Cutaneous Wound Healing

Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus Benedikt Scholtissek, Sabine Zahn, Judith.

Transglutaminase 3 Protects against Photodamage

Epidermolysis Bullosa Simplex Caused by Distal Truncation of BPAG1-e: An Intermediate Generalized Phenotype with Prurigo Papules Iana Turcan, Anna M.G.

Gregory D. Rak, Lisa C. Osborne, Mark C. Siracusa, Brian S

A Conditional Zebrafish MITF Mutation Reveals MITF Levels Are Critical for Melanoma Promotion vs. Regression In Vivo James A. Lister, Amy Capper, Zhiqiang.

Endothelial Cells Promote Pigmentation through Endothelin Receptor B Activation Claire Regazzetti, Gian Marco De Donatis, Houda Hammami Ghorbel, Nathalie.

The Antifibrotic Effect of α2AP Neutralization in Systemic Sclerosis Dermal Fibroblasts and Mouse Models of Systemic Sclerosis Yosuke Kanno, En Shu,

Trim32 Deficiency Enhances Th2 Immunity and Predisposes to Features of Atopic Dermatitis Yuangang Liu, Zhiping Wang, Rachel De La Torre, Ashley Barling,

Mosaicism for a KITLG Mutation in Linear and Whorled Nevoid Hypermelanosis Arthur Sorlin, Annabel Maruani, Marie-Hélène Aubriot-Lorton, Paul Kuentz, Yannis.

Ectodysplasin A Pathway Contributes to Human and Murine Skin Repair

Diagnosing a Primary Leptomeningeal Melanoma by Gene Mutation Signature Johannes van de Nes, Karsten Wrede, Adrian Ringelstein, Mathias Stiller, Susanne.

A New KIT Mutation (N505I) in Acral Melanoma Confers Constitutive Signaling, Favors Tumorigenic Properties, and Is Sensitive to Imatinib Maryline Allegra,

Maik Dahlhoff, Sukalp Muzumdar, Matthias Schäfer, Marlon R. Schneider

A Modeling Conundrum: Murine Models for Cutaneous Wound Healing

A Child with Epidermolytic Ichthyosis from a Parent with Epidermolytic Nevus: Risk Evaluation of Transmission from Mosaic to Germline Michihiro Kono,

Vitali Alexeev, Kyonggeun Yoon Journal of Investigative Dermatology

Overexpression of PRAS40T246A in the Proliferative Compartment Suppresses mTORC1 Signaling, Keratinocyte Migration, and Skin Tumor Development Okkyung.

Transglutaminase 3 Protects against Photodamage

C. Herbert Pratt, Louise A. Dionne, Heather Fairfield, Soheil S

Qiaoli Li, Joshua Kingman, Koen van de Wetering, Sami Tannouri, John P

Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease Jillian M. Richmond,

Volume 15, Issue 3, Pages (February 2005)

Xanthe L. Strudwick, James M. Waters, Allison J. Cowin

A New Lamin A Mutation Associated with Acrogeria Syndrome

Inflammatory Linear Verrucous Epidermal Nevus with a Postzygotic GJA1 Mutation Is a Mosaic Erythrokeratodermia Variabilis et Progressiva Noriko Umegaki-Arao,

Collagen XVII Shedding Suppresses Re-Epithelialization by Directing Keratinocyte Migration and Dampening mTOR Signaling Joanna Jacków, Stefanie Löffek,

In Vivo Role of Vitamin D Receptor Signaling in UVB-Induced DNA Damage and Melanocyte Homeostasis Sharmeen Chagani, Sergiy Kyryachenko, Yoko Yamamoto,

Marie-Thérèse Leccia Journal of Investigative Dermatology

Differential Expression of Matrix Metalloproteinases During Impaired Wound Healing of the Diabetes Mouse Steven J. Wall, Dr, Damon Bevan, David W. Thomas,

Spontaneous Cell Sorting of Fibroblasts and Keratinocytes Creates an Organotypic Human Skin Equivalent C. Kathy Wang, Charlotte F. Nelson, Alice M. Brinkman,

Constitutive Rac Activation Is Not Sufficient to Initiate Melanocyte Neoplasia but Accelerates Malignant Progression Lucy E. Dalton, Jivko Kamarashev,

Johann W. Bauer, Josef Koller, Eva M

TWEAK/Fn14 Signals Mediate Burn Wound Repair

The BRAF Inhibitor Vemurafenib Enhances UV-Induced Skin Carcinogenesis in Beta HPV38 E6 and E7 Transgenic Mice Daniele Viarisio, Karin Müller-Decker,

STIM1, but not STIM2, Is the Calcium Sensor Critical for Sweat Secretion Chang-Yi Cui, Ji Heon Noh, Marc Michel, Myriam Gorospe, David Schlessinger Journal.

Possible Contribution of Fibrocytes to Increased Type I Collagen Synthesis during the Early Stage of Dermal Wound Repair in Human Skin Min Sun, Peiru.

Establishment of Two Mouse Models for CEDNIK Syndrome Reveals the Pivotal Role of SNAP29 in Epidermal Differentiation Stina A. Schiller, Christina Seebode,

Prolonged Activation of ERK Contributes to the Photorejuvenation Effect in Photodynamic Therapy in Human Dermal Fibroblasts Yong Hyun Jang, Gi-Bang Koo,

Postzygotic Mutations in Beta-Actin Are Associated with Becker’s Nevus and Becker’s Nevus Syndrome Emily D. Cai, Bryan K. Sun, Audris Chiang, Anna Rogers,

Paola Zigrino, Isolde Kuhn, Tobias Bäuerle, Jan Zamek, Jay W

The Neurofibromatosis Type 1 (Nf1) Tumor Suppressor is a Modifier of Carcinogen- Induced Pigmentation and Papilloma Formation in C57BL/6 Mice Radhika.

Overexpression of CD109 in the Epidermis Differentially Regulates ALK1 Versus ALK5 Signaling and Modulates Extracellular Matrix Synthesis in the Skin

IL-22 Promotes Fibroblast-Mediated Wound Repair in the Skin

Postzygotic BRAF p.Lys601Asn Mutation in Phacomatosis Pigmentokeratotica with Woolly Hair Nevus and Focal Cortical Dysplasia Paul Kuentz, Cyril Mignot,

AKT1 Gene Mutation Levels Are Correlated with the Type of Dermatologic Lesions in Patients with Proteus Syndrome Marjorie J. Lindhurst, Ji-an Wang, Hadley.

Next-Generation Sequencing of Nevus Spilus–Type Congenital Melanocytic Nevus: Exquisite Genotype–Phenotype Correlation in Mosaic RASopathies Veronica.

Halofuginone, an Inhibitor of Type-I Collagen Synthesis and Skin Sclerosis, Blocks Transforming-Growth-Factor-β-Mediated Smad3 Activation in Fibroblasts

Differential Effects of Neurofibromin Gene Dosage on Melanocyte Development Mugdha Deo, Jenny Li-Ying Huang, Helmut Fuchs, Martin Hrabe de Angelis, Catherine.

Activating HRAS Mutation in Nevus Spilus

Autosomal Recessive Hypotrichosis with Woolly Hair Caused by a Mutation in the Keratin 25 Gene Expressed in Hair Follicles Nikolay V. Zernov, Mikhail.

Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17 Luting Yang, Xueli Fan, Tingting.

Masahiro Hara, Mina Yaar, H

BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma

Bryan K. Sun, Andrea Saggini, Kavita Y

Scleroderma Fibroblasts Demonstrate Enhanced Activation of Akt (Protein Kinase B) In Situ Jae-Bum Jun, Melanie Kuechle, Junki Min, Seung Cheol Shim,

The EGFR Is Required for Proper Innervation to the Skin

A Usual Frameshift and Delayed Termination Codon Mutation in Keratin 5 Causes a Novel Type of Epidermolysis Bullosa Simplex with Migratory Circinate Erythema

RXRα Ablation in Epidermal Keratinocytes Enhances UVR-Induced DNA Damage, Apoptosis, and Proliferation of Keratinocytes and Melanocytes Zhixing Wang,

Frances J.D. Smith, W.H. Irwin McLean

Figure 4 DNM1 mutations affect protein levels and self-dimerization (A) HeLa cells were transfected with green fluorescent protein (GFP)-tagged mutant.

Identification of an mtDNA Mutation Hot Spot in UV-Induced Mouse Skin Tumors Producing Altered Cellular Biochemistry Jana Jandova, Alex Eshaghian, Mingjian.

Redistribution of LRIG Proteins in Psoriasis

Deon G. Uffort, Elizabeth A. Grimm, Julie A. Ellerhorst

AKT1 Gene Mutation Levels Are Correlated with the Type of Dermatologic Lesions in Patients with Proteus Syndrome Marjorie J. Lindhurst, Ji-an Wang, Hadley.

Role and Regulation of STAT3 Phosphorylation at Ser727 in Melanocytes and Melanoma Cells Masanobu Sakaguchi, Masahiro Oka, Tetsushi Iwasaki, Yasuo Fukami,

Presentation transcript:

Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis Anna C. Thomas, Zhiqiang Zeng, Jean-Baptiste Rivière, Ryan O’Shaughnessy, Lara Al-Olabi, Judith St.-Onge, David J. Atherton, Hélène Aubert, Lorea Bagazgoitia, Sébastien Barbarot, Emmanuelle Bourrat, Christine Chiaverini, W. Kling Chong, Yannis Duffourd, Mary Glover, Leopold Groesser, Smail Hadj-Rabia, Henning Hamm, Rudolf Happle, Imran Mushtaq, Jean-Philippe Lacour, Regula Waelchli, Marion Wobser, Pierre Vabres, E. Elizabeth Patton, Veronica A. Kinsler Journal of Investigative Dermatology Volume 136, Issue 4, Pages 770-778 (April 2016) DOI: 10.1016/j.jid.2015.11.027 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Clinical examples of dermatological, ophthalmological, and neurological aspects of phakomatosis pigmentovascularis. (a–c) Dermal melanocytosis and capillary malformation (port wine stain type) on the face, extensive dermal melanocytosis on the back and legs, and capillary malformation on the sole of the right foot. (d) Bilateral scleral melanocytosis with bilateral glaucoma. Capillary malformation and hemihypertrophy are just visible on right side of face. (e) Axial T1-weighed magnetic resonance image of the brain at the level of the lateral ventricles after administration of intravenous gadolinium contrast agent showing bilateral and asymmetrical thickening and enhancement of the pia mater. (Written consent for publication obtained in all cases.) Journal of Investigative Dermatology 2016 136, 770-778DOI: (10.1016/j.jid.2015.11.027) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Sequencing results demonstrating mosaic GNA11 and GNAQ mutations. (a) Sanger sequencing of skin biopsy showing a very low peak in GNA11 at position c.547C>T (p.Arg183Cys) (asterisk). (b) Sanger sequencing of the same skin biopsy deoxyribonucleic acid after restriction enzyme digest of the normal allele, and hemi-nested amplification, revealing the mutation (asterisk). (c) Targeted next-generation sequencing showing low allele percentage mutations in skin but undetectable in blood, GNA11 c.547C>T (p.Arg183Cys) in 5% of reads. (d) GNAQ c.548G>A (p.Arg183Gln) in 6% of reads from skin but undetectable in blood. Journal of Investigative Dermatology 2016 136, 770-778DOI: (10.1016/j.jid.2015.11.027) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Mutant GNA11 leads to activation of downstream signaling pathways. (a) Western blot for Flag, total GNA11, and the phosphorylated and total p38, JNK, ERK and AKT in total protein lysates from HEK293T cells transfected with either vector, wild-type GNA11 (WT), or one of two mutants R183C or Q209L mutant GNA11. (b) Ratio of phosphorylated to total p38, JNK, ERK, and AKT normalized by actin loading control. Bars indicate 1 standard deviation. ∗P < 0.05, unpaired t-test. Journal of Investigative Dermatology 2016 136, 770-778DOI: (10.1016/j.jid.2015.11.027) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Mosaic expression of GNA11 promotes ectopic pigmentary lesions in zebrafish. (a) Images of adult zebrafish mosaic for GNA11, GNA11R183C, or GNA11Q209L expression. Large, ectopic pigmentary lesions are indicated next to white arrows. Dashed box indicates zoomed areas that show detail of pigmentary lesions. (b) Numbers of pigmentary lesions per fish expressing GNA11, GNA11R183C, or GNA11Q209L. Dark circles indicate ectopic pigmentary lesions. White circles indicate fish without pigmentary lesions. (c) Histology hematoxylin and eosin staining of a wild-type and GNA11R183C zebrafish skin at ×100 and ×400 magnification. Melanocytes are clearly visible in the dermis by the black melanin (blue arrows), frequently also in the epidermis (not shown) and in a few cases within underlying muscle (yellow arrow). Journal of Investigative Dermatology 2016 136, 770-778DOI: (10.1016/j.jid.2015.11.027) Copyright © 2016 The Authors Terms and Conditions