Mutations in GDF5 Reveal a Key Residue Mediating BMP Inhibition by NOGGIN

Seemann, Petra; Brehm, Anja; König, Jana; Reißner, Carsten; Stricker, Sigmar; Kuss, Pia; Haupt, Julia; Renninger, Stephanie; Nickel, J. Curtis; Sebald, Walter; Groppe, Jay C.; Plöger, Frank; Pohl, J; Kegler, Mareen Schmidt Von; Walther, Maria; Gaßner, Ingmar; Rusu, Cristina; Janecke, Andreas R.; Dathe, Katarina; Mundlos, Stefan

doi:10.1371/journal.pgen.1000747

Cited by 85 publications

(93 citation statements)

References 42 publications

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“…3 ), as previously reported for the GDF6-Y444N mutation [Seemann et al, 2009;Wang et al, 2016]. In the BMP7-NOG complex, the introduction of a positively charged lysine in the homologous BMP7-N375 position disrupts a hydrophobic pocket accommodating the key noggin residue Pro35 ( Fig.…”

Section: Discussionsupporting

confidence: 63%

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A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss

Berentsen¹,

Haukanes²,

Júlíusson³

et al. 2018

Mol Syndromol

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A 4-generation family with multiple synostoses syndrome type 4 (SYNS4) is reported, the third family identified so far. The phenotype segregated with a previously undescribed Asn399Lys (c.1197C>A) substitution in GDF6. N399 is part of a hydrophobic pocket critical for binding the BMP/GDF antagonist noggin. The N399K substitution renders GDF6 more similar to noggin-resistant members of the BMP family, namely GDF2 and BMP10, both of which contain lysine in the corresponding position. To further define the SYNS4 phenotype, we examined 6 of 9 affected family members. The phenotype was carpal and tarsal synostoses with painful feet after walking, but the condition could also be asymptomatic. Interestingly, unlike the previous SYNS4 families, the family presented here has no history of hearing loss, and a 73-year-old mutation carrier had normal audiometry for his age. Based on structure modelling, BMPR2 binding should not be affected by the GDF6-N399K substitution, unlike the S429R and Y444N mutations found in the 2 other families. Hypothetically, this difference may be related to lack of hearing loss.

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Section: Discussionsupporting

confidence: 63%

“…They all constitute a group of overlapping syndromes, suggested to be called NOG -related symphalangism spectrum disorders [Potti et al, 2011]. GDF5 missense mutations associated with noggin resistance cause the dominant multiple synostoses syndrome type 2 and proximal symphalangism type 1B [Dawson et al, 2006;Seemann et al, 2009;Schwaerzer et al, 2012].…”

mentioning

confidence: 99%

A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss

Berentsen¹,

Haukanes²,

Júlíusson³

et al. 2018

Mol Syndromol

View full text Add to dashboard Cite

show abstract

“…Protein sequence was obtained for each member and aligned using Genious software to determine the presence or absence of an Asparagine residue at amino acid 445. The presence of the N455 indicates a likely Noggin target (Seemann et al 2009). …”

Section: Bioinformatic Identification Of Bmp Family Members In the Dementioning

confidence: 99%

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

2013

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The vertebrate limb is one of the most intensively studied organs in the field of developmental biology. Limb development in tetrapod vertebrates is highly conserved and dependent on the interaction of several important molecular pathways. The bone morphogenetic protein (BMP) signaling cascade is one of these pathways and has been shown to be crucial for several aspects of limb development. Here, we have used a Xenopus laevis transgenic line, in which expression of the inhibitor Noggin is under the control of the heatshock promoter hsp70 to examine the effects of attenuation of BMP signaling at different stages of limb development. Remarkably different phenotypes were produced at different stages, illustrating the varied roles of BMP in development of the limb. Very early limb buds appeared to be refractory to the effects of BMP attenuation, developing normally in most cases. Ectopic limbs were produced by overexpression of Noggin corresponding to a brief window of limb development at about stage 49/50, as recently described by Christen et al. (2012). Attenuation of BMP signaling in stage 51 or 52 tadpoles lead to a reduction in the number of digits formed, resulting in hypodactyly or ectrodactyly, as well as occasional defects in the more proximal tibiafibula. Finally, inhibition at stage 54 (paddle stage) led to the formation of dramatically shortened digits resulting from loss of distal phalanges. Transcriptome analysis has revealed the possibility that more Nogginsensitive members of the BMP family could be involved in limb development than previously suspected. Our analysis demonstrates the usefulness of heat-shock-driven gene expression as an effective method for inhibiting a developmental pathway at different times during limb development.

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“…A number of functional investigations suggested that loss-of-function mutations are responsible for a decrease in GDF5 activity, evident in the underdevelopment and hypersegmentation of the digits in hand and foot resulting in brachydactyly. Conversely, an increase in GDF5 activity, probably due to an alteration of its active site to a resistant form against inhibition by noggin, influences fusing of the joints resulting in symphalangism of the digits in hand and foot [Seemann et al, 2005[Seemann et al, , 2009Yang et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

Novel indel Mutation in the GDF5 Gene Is Associated with Brachydactyly Type C in a Four-Generation Turkish Family

et al. 2014

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Heterozygous loss-of-function mutations of GDF5 are reported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly), and heterozygous gain-of-function mutations, occurring either on the gene itself or through the loss of its inhibitor noggin, result in joint fusion (symphalangism). We present here the clinical and molecular investigation of a family with disproportionate shortness of the second and third fingers which comprises 9 variably affected members spanning 4 generations. In this study, we performed clinical and radiographical examinations of 2 patients of this family, sequencing of GDF5 and 3D protein modeling of the wildtype and mutated polypeptide to predict the structural alteration. Diagnoses were compatible with familial brachydactyly type C. GDF5 analysis revealed a novel heterozygous in-frame indel mutation (c.803_ 827del25ins25), involving the propeptide domain of GDF5 that alters the number of random coil and beta-strand structures, creating a 1-turn-helix at the mutated site. The mutation described here is the second indel reported in GDF5. The previously published homozygous indel mutation affected the TGF-beta like domain and was associated with Du Pan syndrome. The novel mutation reported here presents further allelic heterogeneity and a probable intrafamilial variable clinical expressivity of GDF5.

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Mutations in GDF5 Reveal a Key Residue Mediating BMP Inhibition by NOGGIN

Cited by 85 publications

References 42 publications

A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss

A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

Novel indel Mutation in the GDF5 Gene Is Associated with Brachydactyly Type C in a Four-Generation Turkish Family

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