12755
2013
eng
e1003846
10
9
article
1
2016-02-22
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A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2
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.
PLOS Genetics
10.1371/journal.pgen.1003846
1553-7404
urn:nbn:de:bvb:20-opus-127556
PLoS Genetics 9(10): e1003846. doi:10.1371/journal.pgen.1003846
Elisa Degenkolbe
Jana König
Julia Zimmer
Maria Walther
Carsten Reißner
Joachim Nickel
Frank Plöger
Jelena Raspopovic
James Sharpe
Katharina Dathe
Jacqueline T. Hecht
Stefan Mundlos
Sandra C. Doelken
Petra Seemann
eng
uncontrolled
dominant-negative mutatio
eng
uncontrolled
morphogenetic protein receptors
eng
uncontrolled
brachtydacyly type A2
eng
uncontrolled
BMP
eng
uncontrolled
gene encoding noggin
eng
uncontrolled
growth factor beta
eng
uncontrolled
signal tranduction
eng
uncontrolled
molecular mechanism
eng
uncontrolled
crystal-structure
eng
uncontrolled
differentiation
Menschliche Anatomie, Zytologie, Histologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Lehrstuhl für Tissue Engineering und Regenerative Medizin
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12755/059_Degenkolbe_Plos_Genetics.pdf
11575
2014
eng
108
9
article
1
2015-07-14
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Deletions of exons with regulatory activity at the DYNC1I1 locus are associated with split-hand/split-foot malformation: array CGH screening of 134 unrelated families
Background: A growing number of non-coding regulatory mutations are being identified in congenital disease. Very recently also some exons of protein coding genes have been identified to act as tissue specific enhancer elements and were therefore termed exonic enhancers or "eExons".
Methods: We screened a cohort of 134 unrelated families with split-hand/split-foot malformation (SHFM) with high resolution array CGH for CNVs with regulatory potential.
Results: In three families with an autosomal dominant non-syndromic SHFM phenotype we detected microdeletions encompassing the exonic enhancer (eExons) 15 and 17 of DYNC1I1. In a fourth family, who had hearing loss in addition to SHFM, we found a larger deletion of 510 kb including the eExons of DYNC1I1 and, in addition, the human brain enhancer hs1642. Exons 15 and 17 of DYNC1I1 are known to act as tissue specific limb enhancers of DLX5/6, two genes that have been shown to be associated with SHFM in mice. In our cohort of 134 unrelated families with SHFM, deletions of the eExons of DYNC1I1 account for approximately 3% of the cases, while 17p13.3 duplications were identified in 13% of the families, 10q24 duplications in 12%, and TP63 mutations were detected in 4%.
Conclusions: We reduce the minimal critical region for SHFM1 to 78 kb. Hearing loss, however, appears to be associated with deletions of a more telomeric region encompassing the brain enhancer element hs1642. Thus, SHFM1 as well as hearing loss at the same locus are caused by deletion of regulatory elements. Deletions of the exons with regulatory potential of DYNC1I1 are an example of the emerging role of exonic enhancer elements and their implications in congenital malformation syndromes.
Orphanet Journal of Rare Diseases
10.1186/s13023-014-0108-6
1750-1172
25231166
urn:nbn:de:bvb:20-opus-115759
Orphanet Journal of Rare Diseases 2014 9:108. DOI:10.1186/s13023-014-0108-6
Naeimeh Tayebi
Aleksander Jamsheer
Ricarda Flöttmann
Anna Sowinska-Seidler
Sandra C. Doelken
Barbara Oehl-Jaschkowitz
Wiebke Hülsemann
Rolf Habenicht
Eva Klopocki
Sefan Mundlos
Malte Spielmann
eng
uncontrolled
SHFM
eng
uncontrolled
DLX5/6
eng
uncontrolled
DYNC1I1
eng
uncontrolled
regulatory mutations
eng
uncontrolled
eExons
eng
uncontrolled
tissue-specific enhancers
eng
uncontrolled
hand/foot malformation
eng
uncontrolled
II citrullinemia
eng
uncontrolled
limb development
eng
uncontrolled
human disease
Medizin und Gesundheit
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11575/059_Teyebi_Orphanet_Journal_of_ Rare_Diseases.pdf