Insulin-Like Growth Factor-I Gene Analysis in Subjects with Constitutionally Variant Stature

Abstract

ABSTRACT. The IGF-I gene from leukocyte DNA of a control population of normal stature was studied using Southern blotting. Restriction fragment lengths for 21 enzymes were determined and three restriction fragment length polymorphisms (RFLP) were found (EcoRV, HindIII, and PvuII). In addition, the IGF-I gene of 64 constitutionally short subjects, five Pygmies, and 10 constitutionally tall subjects was analyzed. No IGF-I gene alterations were detectable by Southern blot in any of these conditions. Linkage analysis using genetic markers (RFLP) yielded results that were uninformative for five constitutionally short families investigated, owing to the limited number of RFLP and their low incidence (17% for the 5.2-kb HindIII, 5-kb PvuII RFLP alleles, and 13% for the 13-kb EcoRV RFLP allele). The EcoRV RFLP was found to map near Exon 1. The incidence of the 13-kb polymorphic allele with EcoRV proved to be lower (4%) in the group with constitutionally short stature than in controls. These results could suggest that modifications in the region of the IGF-I gene may be involved in constitutionally short subjects. (Pediatr Res 27:488-491, 1990) Abbreviations constitutionally variant stature were selected on the basis of criteria defined previously (3, 4). Sixty-four short subjects were studied (55 of whom were unrelated). Fifty-eight were children and adolescents, and six were fully grown. Ht was below -2 SD for the French population (7), the average being -2.7 SD. Birth size was 49 cm a 1.2 (mean a SD). The mean body mass index (wt/ht2) was 15.8 k 1.6, which is within the normal range. Five families were also investigated, comprising 24 subjects of whom 13 were constitutionally short. All short subjects had GH levels exceeding 14 ng/mL after ornithine infusion and the mean of the GH peaks (22.7 k 7.3 ng/mL, mean + SD) was no different from that of normals (8). Ten constitutionally tall subjects (nine children and adolescents and one adult) were studied (ht above +2 SD, the mean being +3.4 SD). In all cases, wt was within the normal range (mean f I SD for ht). Thyroid hormone levels were normal in all subjects (free T4: 14.2 + 2.9 pg/mL, TSH:

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

“…As in previous studies, 20,21,55 we could find no polymorphism in the 5 0 region of the IGF1 gene associated with stature among Central African pygmies and non-pygmies. As a recombination hotspot separates most of the IGF1 gene from its 5 0 region (see the recombination rate estimated from HapMap Phase 2 56 in Supplementary Figure S1), we re-sequenced other portions of this gene and found that a SNP (rs11831436) in the second intron presented an outlying value of the genetic distance between the Baka pygmies and the Nzimé non-pygmies.…”

“…Most of the primers were designed using Primer 3 26 and others were adapted from previous studies. 21,27,28 Primer sequences can be found in Supplementary Table S1. Amplifications were performed using standard PCR conditions (available upon request).…”

“…18 Small regions of the GHR and IGF1 genes have been previously tested for association with the stature of African pygmies with negative results. [18][19][20][21] A recent genome-wide study has identified regions in the genome that might be involved in the difference in stature observed between pygmies from Cameroon and their non-pygmy neighbors, although this signal was not significant. 22 Some of these regions contain genes linked to the GH-IGF1 signaling pathway.…”

Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation

“…Common polymorphisms in GH1 (Hasegawa et al 2000;Millar et al 2003) and IGF1 Schneid et al 1990;Vaessen et al 2001) have been associated with height variation. However, these initial association Wndings have not been validated in other replication populations and they were identiWed in relatively small cohorts, lowering the likelihood that these represent robust associations (Ioannidis et al 2003;Lohmueller et al 2003;Wacholder et al 2004).…”

Constitutionally Short Stature: Analysis of the Insulin-Like Growth Factor-I Gene and the Human Growth Hormone Gene Cluster

“…In one of the studies, a significantly decreased prevalence of one allele of an EcoRV RFLP associated with the IGF-I gene was found in children with CSS (12), and it was suggested that this might indicate a role for minor abnormalities of the IGF-I gene in CSS.…”