Brachydactyly type A2 associated with a defect in proGDF5 processing

Plöger, Frank; Seemann, Petra; Kegler, Mareen Schmidt-von; Lehmann, Kerstin; Seidel, Jörg; Kjaer, Klaus; Pohl, J; Mundlos, Stefan

doi:10.1093/hmg/ddn012

Cited by 60 publications

(57 citation statements)

References 52 publications

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“…The Arg377Trp mutation is located within the recognition motif at the processing site of GDF5 where the sequence RRKRR changes to WRKRR. Similar changes at neighbouring amino acids, Arg378Gln and Arg380Gln, were associated with Du Pan syndrome and brachydactyly type A2, respectively, and they were shown to interfere with the cleavage of proGDF5 at the recognition site [7,8]. We postulate that p.Arg377Trp can be considered a mutant allele, taking into account the prediction tests, the conserved codon of the protein affected, the motif of the protein altered and the presence of another mutation in a Pakistani consanguineous family having a member with the same rare disease.…”

Section: Resultsmentioning

confidence: 90%

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5

et al. 2015

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Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia characterized by severe dwarfism with marked micromelia and deformation of the upper and lower limbs, with a proximodistal gradient of severity. CDMP1 gene mutations have been associated with Grebe syndrome, Hunter-Thompson syndrome, Du Pan syndrome and brachydactyly type C. The proband is a 4-year-old boy, born of consanguineous Pakistani parents. Radiographic imaging revealed features typical of Grebe syndrome: severe shortening of the forearms with an acromesomelic pattern following a proximodistal gradient, with distal parts more severely affected than medial parts; hypoplastic hands, with the phalangeal zone more affected than the metacarpal zone; and severe hypoplastic tibial/femoral zones in both limbs. After molecular analyses, the p.Arg377Trp variant in a homozygous pattern was identified in the CDMP1 gene in the affected child. In silico and structural analyses predicted the p.Arg377Trp amino acid change to be pathogenic. Of the 34 mutations described in the CDMP1 gene, four different missense mutations have been associated with Grebe syndrome. The CDMP1 gene encodes growth differentiation factor 5 (GDF5), which plays a role in regulation of limb patterning, joint formation and distal bone growth. Homozygous mutations in the mature domain of GDF5 result in severe limb malformations such as the Grebe type or the Hunter-Thompson type of acromesomelic chondrodysplasia. The p.Arg377Trp mutation is located within the recognition motif at the processing site of GDF5 where the sequence RRKRR changes to WRKRR. The genotype-phenotype correlation allowed not only confirmation of the clinical diagnosis but also appropriate genetic counselling to be offered to this family.

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Section: Resultsmentioning

confidence: 90%

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5

et al. 2015

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“…Our results suggest that these mutations could result in a more stable or active version of Noggin protein. Another class of brachydactyly (BDA2) results from either mutation of gdf5 (Ploger et al 2008), dominant negative mutation of the receptor BmpR1B (Lehmann et al 2003) or duplication of a conserved regulatory element in the Bmp2 gene (Dathe et al 2009). In fact, all documented examples of isolated brachydactyly can be linked directly or indirectly to altered BMP signal transduction (Temtamy & Aglan, 2008).…”

Section: Ectopic Limb Formation Can Results From Noggin Over-expressionmentioning

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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“…Top categories included upregulation of apoptotic and BMP signaling genes and the downregulation of genes involved in chondrogenic differentiation (Table S2). In addition, several of the significantly downregulated genes are known to cause human syndromes with short digits (brachydactyly), including Gdf5, Bmpr1b and noggin (Nog) (Al-Qattan et al, 2015;Byrnes et al, 2010;Lehmann et al, 2007Lehmann et al, , 2003Ploger et al, 2008).…”

Section: Genomic Analysis Of Prmt5 Cko Limbsmentioning

confidence: 99%

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

Norrie

et al. 2016

Development

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During embryonic development, undifferentiated progenitor cells balance the generation of additional progenitor cells with differentiation. Within the developing limb, cartilage cells differentiate from mesodermal progenitors in an ordered process that results in the specification of the correct number of appropriately sized skeletal elements. The internal pathways by which these cells maintain an undifferentiated state while preserving their capacity to differentiate is unknown. Here, we report that the arginine methyltransferase PRMT5 has a crucial role in maintaining progenitor cells. Mouse embryonic buds lacking PRMT5 have severely truncated bones with wispy digits lacking joints. This novel phenotype is caused by widespread cell death that includes mesodermal progenitor cells that have begun to precociously differentiate into cartilage cells. We propose that PRMT5 maintains progenitor cells through its regulation of Bmp4. Intriguingly, adult and embryonic stem cells also require PRMT5 for maintaining pluripotency, suggesting that similar mechanisms might regulate lineage-restricted progenitor cells during organogenesis.

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Brachydactyly type A2 associated with a defect in proGDF5 processing

Cited by 60 publications

References 52 publications

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5

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

PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud

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