Journal
HUMAN MUTATION
Volume 36, Issue 11, Pages 1043-1047Publisher
WILEY-BLACKWELL
DOI: 10.1002/humu.22853
Keywords
IGF1R; IGF1; SHORT syndrome; neonatal progeroid syndrome; PI3K
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Funding
- Italian Ministry of Health (Ricerca Corrente)
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Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R-mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations.
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