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Biotech / Medical : Regeneron Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (567)	9/24/2001 7:35:13 PM
From: keokalani'nui	Read Replies (1) \| Respond to of 3557

: Proc Natl Acad Sci U S A 2001 Sep 18; [epub ahead of print] Related Articles, Books, LinkOut Human disease-causing NOG missense mutations: Effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML. Department of Genetics and Center for Human Genetics, and Department of Orthopaedics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Molecular and Cell Biology, Division of Genetics and Development, University of California, Berkeley, CA 94720. 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. ______________ It's significance is totally lost on me. Pretty good journal I hear. Wilder