A New Subtype of Brachydactyly Type B Caused by Point Mutations in the Bone Morphogenetic Protein Antagonist NOGGIN

Abstract

Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the majority of patients. In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system. Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface.

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

“…Brachydactyly is closely associated with altered BMP signaling in humans. Point mutations in the Noggin coding region result in brachydactyly type B (BDB), in which there is a deficiency of the distal elements of the fingers and toes (Lehmann et al 2007). These Noggin mutations are not loss of function and are predicted to still bind Gdf5.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Short distal phalanges in combination with symphalangism, fusion of carpal and tarsal bones and partial cutaneous syndactyly are characteristic skeletal malformations in BDB2 patients. Point mutations within the NOGGIN (NOG) gene cause reduced binding capacity to BMP ligands and result in reduced sequestration of BMP ligand by the mutant protein, which shifts the state of the BMP signaling pathway balance toward activation (Lehmann et al 2007) and results in disruption of digit patterning. (Komatsu et al 2013).…”

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

“…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).…”