title: Alu-mediated recombination defect in IGF1R: haploinsufficiency in a patient with short stature.
abstract: BACKGROUND
  The insulin-like growth factor (IGF) receptor (IGF1R) is essential for normal development and growth. IGF1R mutations cause IGF-1 resistance resulting in intrauterine and postnatal growth failure. The phenotypic spectrum related to IGF1R mutations remains to be fully understood.
  
  
  METHODS
  Auxological and endocrinological data of a patient identified previously were assessed. The patient's fibroblasts were studied to characterize the IGF1R deletion, mRNA fate, protein expression and signalling capabilities.
  
  
  RESULTS
  The boy, who carries a heterozygous IGF1R exon 6 deletion caused by Alu element-mediated recombination and a heterozygous SHOX variant (p.Met240Ile), was born appropriate for gestational age but developed proportionate short stature postnatally. IGF-1 levels were low-normal. None of the stigmata associated with SHOX deficiency or sporadically observed in IGF1R mutation carriers were present. Nonsense-mediated mRNA decay led to a substantial decline of IGF1R dosage and IGF-1-dependent receptor autophosphorylation but not impaired downstream signalling.
  
  
  CONCLUSIONS
  We present the first detailed report of an intragenic IGF1R deletion identified in a patient who, apart from short stature, deviates from all established markers that qualify a growth-retarded child for IGF1R analysis. Although such children will usually escape routine clinical mutation screenings, they can contribute to the understanding of factors and mechanisms that cooperate with the IGF1R.
authors.affiliation: University Hospital for Children and Adolescents, Centre for Paediatric Research, Leipzig, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Harmel
authors.forename: Gerhard
authors.initials: G
authors.lastname: Binder
authors.forename: Anja
authors.initials: A
authors.lastname: Barnikol-Oettler
authors.forename: Janina
authors.initials: J
authors.lastname: Caliebe
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.forename: Monique
authors.initials: M
authors.lastname: Losekoot
authors.forename: Michael B
authors.initials: MB
authors.lastname: Ranke
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Rappold
authors.forename: Marina
authors.initials: M
authors.lastname: Schlicke
authors.forename: Heike
authors.initials: H
authors.lastname: Stobbe
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Roland
authors.initials: R
authors.lastname: Pfäffle
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klammt
mesh_terms: D020087:Alu Elements / Q000502:physiology*; D001827:Body Height; D002648:Child; D004392:Dwarfism / Q000235:genetics*; D057238:Growth Charts; D057895:Haploinsufficiency; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D011995:Recombination, Genetic; D000074122:Short Stature Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D017526:Receptor, IGF Type 1