title: Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance.
abstract: We identified an amino acid change (p.G92E) in the Bone Morphogenetic Protein antagonist NOGGIN in a 22-month-old boy who presented with a unilateral brachydactyly type B phenotype. Brachydactyly type B is a skeletal malformation that has been associated with increased Bone Morphogenetic Protein pathway activation in other patients. Previously, the amino acid change p.G92E in NOGGIN was described as causing fibrodysplasia ossificans progressiva, a rare genetic disorder characterized by limb malformations and progressive heterotopic bone formation in soft tissues that, like Brachydactyly type B, is caused by increased activation of Bone Morphogenetic Protein signaling. To determine whether G92E-NOGGIN shows impaired antagonism that could lead to increased Bone Morphogenetic Protein signaling, we performed functional assays to evaluate inhibition of BMP signaling. Interestingly, wt-NOGGIN shows different inhibition efficacies towards various Bone Morphogenetic Proteins that are known to be essential in limb development. However, comparing the biological activity of G92E-NOGGIN with wt-NOGGIN, we observed that G92E-NOGGIN inhibits activation of bone morphogenetic protein signaling with equal efficiency as wt-NOGGIN, supporting that G92E-NOGGIN does not cause pathological effects. Genetic testing of the child's parents revealed the same amino acid change in the healthy father, further supporting that p.G92E is a neutral amino acid substitution in NOGGIN. We conclude that p.G92E represents a rare polymorphism of the NOGGIN gene-- causing neither brachydactyly nor fibrodysplasia ossificans progressiva. This study highlights that a given genetic variation should not be considered pathogenic unless supported by functional analyses.
authors.affiliation: Berlin Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Zimmer
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Doelken
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Jay C
authors.initials: JC
authors.lastname: Groppe
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000737:chemistry / Q000378:metabolism; D059327:Brachydactyly / Q000000981:diagnostic imaging / Q000209:etiology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002642:Chick Embryo; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D011859:Radiography; D000099176:Noggin Protein
chemical_list: D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D000099176:Noggin Protein