title: Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations.
abstract: BACKGROUND
  IGF-I deficiency may result from impairment of GH secretion or action, or from defects in IGF-I synthesis, transport, or action. Complete deficiency of the acid-labile subunit (ALS), previously described in two male patients, the only known inherited alteration in IGF-I transport, is characterized by severe circulating IGF-I and IGF binding protein (IGFBP)-3 deficiency with only mild growth retardation.
  
  
  OBJECTIVE
  Our objective was to study the characterization, at biochemical and molecular levels, of the cause for severe circulating IGF-I and IGFBP-3 deficiency in a male patient with mild growth retardation.
  
  
  METHODS
  We report an adolescent male with delayed growth and pubertal development (Tanner stage I, -2.00 sd score for height at the age of 15.3 yr), profound circulating IGF-I and IGFBP-3 deficiency, and poor response to GH treatment.
  
  
  RESULTS
  The index case, as well as one of his brothers, and his sister were found to be compound heterozygotes for two novel IGFALS gene mutations: C540R, a missense point mutation; and S195_197Rdup, a 9-bp duplication. The parents and youngest brother were found to be carriers for one of these two mutations. The three affected siblings had marked reduction of IGF-I and IGFBP-3 levels, undetectable serum levels of ALS, inability to form ternary complexes, and moderate insulin resistance. All of them attained a normal near-adult height (between -1.0 and -0.5 sd score), which was nonetheless lower than that of their heterozygous brother. The IGF system was only modestly affected in the heterozygous carriers.
  
  
  CONCLUSIONS
  This study confirms the critical role of ALS in forming ternary complexes and the maintenance of normal levels of IGF-I and IGFBP-3. Insulin resistance, pubertal delay in male patients, and poor GH responsiveness seem to be frequent findings in ALS deficiency. However, haploinsufficiency of the IGFALS gene has no discernible clinical effects with only modest impact on the IGF system.
authors.affiliation: Centro de Investigaciones Endocrinológicas, Hospital de Niños "R. Gutiérrez," Gallo 1330, 1425 Buenos Aires, Argentina. hdomene@cedie.org.ar
authors.forename: Horacio M
authors.initials: HM
authors.lastname: Domené
authors.forename: Paula A
authors.initials: PA
authors.lastname: Scaglia
authors.forename: Aida
authors.initials: A
authors.lastname: Lteif
authors.forename: Farid H
authors.initials: FH
authors.lastname: Mahmud
authors.forename: Salman
authors.initials: S
authors.lastname: Kirmani
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
authors.forename: Patricia
authors.initials: P
authors.lastname: Bedecarrás
authors.forename: Mariana
authors.initials: M
authors.lastname: Gutiérrez
authors.forename: Héctor G
authors.initials: HG
authors.lastname: Jasper
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D050260:Carbohydrate Metabolism / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002850:Chromatography, Gel; D004252:DNA Mutational Analysis; D005260:Female; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics*; D012739:Gonadal Steroid Hormones / Q000097:blood; D006128:Growth / Q000235:genetics / Q000502:physiology; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011627:Puberty / Q000235:genetics / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D012739:Gonadal Steroid Hormones; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D008055:Lipids; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I