期刊
EMBO MOLECULAR MEDICINE
卷 8, 期 4, 页码 363-374出版社
WILEY
DOI: 10.15252/emmm.201506106
关键词
bone; delayed growth; growth hormone; IGF-binding proteins; IGF bioavailability
资金
- Fondos de Investigacion Sanitaria and fondos FEDER [PI100747, PI1302195, PI1302481]
- Ministerio de Ciencia e Innovacion [BFU2011-27492, BFU2014-51836-C2-2-R]
- Centro de Investigacion Biomedica en Red Fisiopatologia de Obesidad y Nutricion (CIBEROBN)
- Instituto de Salud Carlos III
- Fundacion Endocrinologia y Nutricion
- Catalan Government [2014SGR1468]
- Catalan Government (ICREA Academica)
- Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health [K23HD07335]
- Danish Council for Independent Research
- Novo Nordisk Foundation
- CIBER for Rare Diseases (CIBERER)
Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs.
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