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Resultados filtrados por Publicador: The National Academy of Sciences
‣ Human disease-causing NOG missense mutations: Effects on noggin secretion, dimer formation, and bone morphogenetic protein binding
Fonte: The National Academy of Sciences
Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
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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.
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