TY  - JOUR
A1  - Degenkolbe, Elisa
A1  - König, Jana
A1  - Zimmer, Julia
A1  - Walther, Maria
A1  - Reißner, Carsten
A1  - Nickel, Joachim
A1  - Plöger, Frank
A1  - Raspopovic, Jelena
A1  - Sharpe, James
A1  - Dathe, Katharina
A1  - Hecht, Jacqueline T.
A1  - Mundlos, Stefan
A1  - Doelken, Sandra C.
A1  - Seemann, Petra
T1  - A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2
JF  - PLOS Genetics
N2  - Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5 W-414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain-and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.
KW  - dominant-negative mutatio
KW  - morphogenetic protein receptors
KW  - brachtydacyly type A2
KW  - BMP
KW  - gene encoding noggin
KW  - growth factor beta
KW  - signal tranduction
KW  - molecular mechanism
KW  - crystal-structure
KW  - differentiation
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127556
SN  - 1553-7404
VL  - 9
IS  - 10
ER  - 
TY  - JOUR
A1  - Lodde, Georg
A1  - Forschner, Andrea
A1  - Hassel, Jessica
A1  - Wulfken, Lena M.
A1  - Meier, Friedegund
A1  - Mohr, Peter
A1  - Kähler, Katharina
A1  - Schilling, Bastian
A1  - Loquai, Carmen
A1  - Berking, Carola
A1  - Hüning, Svea
A1  - Schatton, Kerstin
A1  - Gebhardt, Christoffer
A1  - Eckardt, Julia
A1  - Gutzmer, Ralf
A1  - Reinhardt, Lydia
A1  - Glutsch, Valerie
A1  - Nikfarjam, Ulrike
A1  - Erdmann, Michael
A1  - Stang, Andreas
A1  - Kowall, Bernd
A1  - Roesch, Alexander
A1  - Ugurel, Selma
A1  - Zimmer, Lisa
A1  - Schadendorf, Dirk
A1  - Livingstone, Elisabeth
T1  - Factors influencing the adjuvant therapy decision: results of a real-world multicenter data analysis of 904 melanoma patients
JF  - Cancers
N2  - Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.
KW  - melanoma
KW  - adjuvant treatment
KW  - checkpoint blocker
KW  - targeted therapy
KW  - BRAF
KW  - PD-1
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239583
SN  - 2072-6694
VL  - 13
IS  - 10
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  -