title: Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.
abstract: Secreted noggin protein regulates bone morphogenetic protein activity during development. In mice, a complete loss of noggin protein leads to multiple malformations including joint fusion, whereas mice heterozygous for Nog loss-of-function mutations are normal. In humans, heterozygous NOG missense mutations have been found in patients with two autosomal dominant disorders of joint development, multiple synostosis syndrome (SYNS1) and a milder disorder proximal symphalangism (SYM1). This study investigated the effect of one SYNS1 and two SYM1 disease-causing missense mutations on the structure and function of noggin. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant noggin with wild-type noggin, to resemble the heterozygous state, did not interfere with wild-type noggin secretion. These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. Therefore, we conclude that noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. Surprisingly, in contrast to the COS-7 cell studies, the SYNS1 mutant was able to form dimers in Xenopus laevis oocytes. This finding indicates that there also exist species-specific differences in the ability to process mutant noggin polypeptides.
authors.affiliation: Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: J
authors.initials: J
authors.lastname: Marcelino
authors.forename: C M
authors.initials: CM
authors.lastname: Sciortino
authors.forename: M F
authors.initials: MF
authors.lastname: Romero
authors.forename: L M
authors.initials: LM
authors.lastname: Ulatowski
authors.forename: R T
authors.initials: RT
authors.lastname: Ballock
authors.forename: A N
authors.initials: AN
authors.lastname: Economides
authors.forename: P M
authors.initials: PM
authors.lastname: Eimon
authors.forename: R M
authors.initials: RM
authors.lastname: Harland
authors.forename: M L
authors.initials: ML
authors.lastname: Warman
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019556:COS Cells; D002352:Carrier Proteins; D002522:Chlorocebus aethiops; D019281:Dimerization; D004220:Disulfides; D005260:Female; D006801:Humans; D020125:Mutation, Missense; D009865:Oocytes / Q000502:physiology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013580:Synostosis / Q000235:genetics; D014162:Transfection; D014982:Xenopus laevis; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004220:Disulfides; D011506:Proteins; D011994:Recombinant Proteins; D000099176:Noggin Protein