A New Homozygous IGF1R Variant Defines a Clinically Recognizable Incomplete Dominant form of SHORT Syndrome

作者：Prontera Paolo^*; Micale Lucia; Verrotti Alberto; Napolioni Valerio; Stangoni Gabriela; Merla Giuseppe

来源：Human Mutation, 2015, 36(11): 1043-1047.

DOI：10.1002/humu.22853

• IGF1R
• IGF1
• SHORT syndrome
• neonatal progeroid syndrome
• PI3K

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.

• 出版日期2015-11
• 单位Perugia