TY  - JOUR
A1  - Thomas, Anna C.
A1  - Zeng, Zhiqiang
A1  - Rivière, Jean-Baptiste
A1  - O'Shaughnessy, Ryan
A1  - Al-Olabi, Lara
A1  - St.-Onge, Judith
A1  - Atherton, David J.
A1  - Aubert, Hélène
A1  - Bagazgoitia, Lorea
A1  - Barbarot, Sébastien
A1  - Bourrat, Emmanuelle
A1  - Chiaverini, Christine
A1  - Chong, W. Kling
A1  - Duffourd, Yannis
A1  - Glover, Mary
A1  - Groesser, Leopold
A1  - Hadj-Rabia, Smail
A1  - Hamm, Henning
A1  - Happle, Rudolf
A1  - Mushtaq, Imran
A1  - Lacour, Jean-Philippe
A1  - Waelchli, Regula
A1  - Wobser, Marion
A1  - Vabres, Pierre
A1  - Patton, E. Elizabeth
A1  - Kinsler, Veronica A.
T1  - Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis
JF  - Journal of Investigative Dermatology
N2  - Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Ga subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11\(^R183C\) and GNA11\(^Q209L\) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11\(^R183C\) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.
KW  - uveal melanoma
KW  - G Protein
KW  - dermal melanocytosis
KW  - Sturge-Weber syndrom
KW  - cesioflammea
KW  - germline
KW  - phakomatosis pigmentovascularis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189689
VL  - 136
IS  - 4
ER  - 
TY  - JOUR
A1  - Ballin, Nadja
A1  - Hotz, Alrun
A1  - Bourrat, Emmanuelle
A1  - Küsel, Julia
A1  - Oji, Vinzenz
A1  - Bouadjar, Bakar
A1  - Brognoli, Davide
A1  - Hickman, Geoffroy
A1  - Heinz, Lisa
A1  - Vabres, Pierre
A1  - Marrakchi, Slaheddine
A1  - Leclerc‐Mercier, Stéphanie
A1  - Irvine, Alan
A1  - Tadini, Gianluca
A1  - Hamm, Henning
A1  - Has, Cristina
A1  - Blume‐Peytavi, Ulrike
A1  - Mitter, Diana
A1  - Reitenbach, Marina
A1  - Hausser, Ingrid
A1  - Zimmer, Andreas D.
A1  - Alter, Svenja
A1  - Fischer, Judith
T1  - Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4
JF  - Human Mutation
N2  - Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa‐Like Domain‐Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype–phenotype correlations.
KW  - ARCI
KW  - ARCI EM type III
KW  - collodion baby
KW  - ichthyosis
KW  - NIPAL4
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212747
VL  - 40
IS  - 12
ER  -