IGF-I Deficiency and Growth Failure: Association with Mutations in the Intracellular Domain of the Growth Hormone Receptor Gene. ▴ 541

Abstract

Abnormalities of the extracellular domain of the growth hormone (GH) receptor gene have been identified as possible links to the short stature of certain children. Recently, we had the chance to investigate a young boy with profound growth retardation and a novel mutation in theintracellular domain of the GH receptor (GHR) gene. At 6 10/12 yrs he was evaluated for short stature (Ht:-4 SDS), despite normal weight (50% ht for wt curve). Bone age was 4 6/12 yrs. Parents' heights were normal (Mother:-0.3, Father: -0.1 SDS). Peak GH response to secretagogues was: 15.3 ng/mL; extracted IGF-I: 57 ng/mL (88-474); IGFBP3: 1.5 mg/L (0.9-4.1); GHBP: 156 pmoL/L (63-250). An IGF-I generation test performed (0.06 mg/kg·d for 5d) failed to raise his circulating IGF-I concentrations (68 ng/mL). WBC's from the patient and immediate family were transformed using EBV, and the GHR gene analyzed using PCR and single strand conformational polymorphism analysis(SSCA) of each of the coding exons. SSCA of exons 2 through 10 of the GHR gene revealed 4 aberrant bands for exon 10, which encodes for theintracellular domain of the GHR. The proband carried 2 single base pair changes: one, a silent base pair substitution in codon 473 (which encodes for serine); another in codon 478 (G to A) causing an amino acid substitution(ALATHR). His mother carried the 478Thr mutation, and the father the silent 473Ser mutation. A 4 year old sister (HT: -0.5 SDS) carried the wild type receptor, and a 6 year old sister (HT: -1.9 SDS) has an identical genotype as the proband. Since the patient is of hispanic (Puerto Rican) parents we extended the analysis to 10 Puerto Rican and 24 caucasian controls. Neither of these GHR changes were found in these 34 individuals.