Expression of serum insulin-like growth factors, insulin-like growth factor-binding proteins, and the growth hormone-binding protein in heterozygote relatives of Ecuadorian growth hormone receptor deficient patients

Paul J. Fielder, Jaime Guevara-Aguirre, Arlan L. Rosenbloom, Lena Carlsson, Raymond L. Hintz, Ronald (Ron) Rosenfeld

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Recently, an isolated population of apparent GH-receptor deficient (GHRD) patients has been identified in the Loja province of southern Ecuador. These individuals presented many of the physical and biochemical phenotypes characteristic of Laron-Syndrome and are believed to have a defect in the GH-receptor gene. In this study, we have compared the biochemical phenotypes between the affected individuals and their parents, considered to be obligate heterozygotes for the disorder. Serum GH, insulin-like growth factor I and II (IGF-I and IGF-II) levels were measured by RIA Insulin-like growth factor binding proteins. (IGFBPs) were measured by Western ligand blotting (WLB) of serum samples, following separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and relative quantitation of serum IGFBPs was performed with a scanning laser densitometer. Serum GH-binding protein (GHBP) levels were measured with a ligand-mediated immunofunctional assay using a monoclonal antibody raised against the GHBP. These values were then compared to values obtained from normal, sex-matched adult Ecuadorian controls, to determine if the above parameters were abnormal in the heterozygotes. The serum IGF-I levels of the GHRD patients were less than 13% of control values for adults and 2% for children. However, the IGF-I levels of both the mothers and fathers were not significantly different from that of the control population. The serum IGF-II levels of the GHRD patients were approximately 20% of control values for adults and 12% for the children. The IGF-II levels of the mothers were reduced, but were not significantly different from that of the control population. However, IGF-II levels of the fathers were significantly lower than those of controls (64% of control male levels). WLB analysis of serum IGFBP levels of the affected subjects demonstrated increased IGFBP-2 and decreased IGFBP-3, suggesting an inverse relationship between these IGFBPs. The GHRD patients who had the lowest serum IGFBP-3 levels (as measured by WLB) demonstrated a serum protease activity that could proteolyze 125I-IGFBP-3. GHRD patients who had higher serum IGFBP-3 levels lacked this serum protease activity. There were no differences in the serum IGFBP profiles of the mothers or the fathers for either IGFBP-2 or IGFBP-3, and serum from both groups lacked the ability to significantly proteolyze 125I-IGFBP-S. While GHRD patients had very low levels of serum GHBP, some patients did have measurable GHBP levels. The mean GHBP levels of the mothers (76% of control females) and father (64% of control males), while reduced, did not significantly differ from those of controls. Thus, while serum IGF-II and GHBP levels were somewhat reduced in the parents of the GHRD patients, they do not appear to provide a reliable biochemical marker for heterozygosity of the defective gene.

Original languageEnglish (US)
Pages (from-to)743-750
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume74
Issue number4
StatePublished - Apr 1992
Externally publishedYes

Fingerprint

Somatotropin Receptors
Insulin-Like Growth Factor Binding Proteins
Somatomedins
Heterozygote
Insulin-Like Growth Factor II
Insulin-Like Growth Factor Binding Protein 3
Serum
Insulin-Like Growth Factor I
Insulin-Like Growth Factor Binding Protein 2
Ligands
Fathers
Mothers
Peptide Hydrolases
Genes
Densitometers
Western Blotting
somatotropin-binding protein
Level control
Electrophoresis
Sodium Dodecyl Sulfate

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Expression of serum insulin-like growth factors, insulin-like growth factor-binding proteins, and the growth hormone-binding protein in heterozygote relatives of Ecuadorian growth hormone receptor deficient patients. / Fielder, Paul J.; Guevara-Aguirre, Jaime; Rosenbloom, Arlan L.; Carlsson, Lena; Hintz, Raymond L.; Rosenfeld, Ronald (Ron).

In: Journal of Clinical Endocrinology and Metabolism, Vol. 74, No. 4, 04.1992, p. 743-750.

Research output: Contribution to journalArticle

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abstract = "Recently, an isolated population of apparent GH-receptor deficient (GHRD) patients has been identified in the Loja province of southern Ecuador. These individuals presented many of the physical and biochemical phenotypes characteristic of Laron-Syndrome and are believed to have a defect in the GH-receptor gene. In this study, we have compared the biochemical phenotypes between the affected individuals and their parents, considered to be obligate heterozygotes for the disorder. Serum GH, insulin-like growth factor I and II (IGF-I and IGF-II) levels were measured by RIA Insulin-like growth factor binding proteins. (IGFBPs) were measured by Western ligand blotting (WLB) of serum samples, following separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and relative quantitation of serum IGFBPs was performed with a scanning laser densitometer. Serum GH-binding protein (GHBP) levels were measured with a ligand-mediated immunofunctional assay using a monoclonal antibody raised against the GHBP. These values were then compared to values obtained from normal, sex-matched adult Ecuadorian controls, to determine if the above parameters were abnormal in the heterozygotes. The serum IGF-I levels of the GHRD patients were less than 13{\%} of control values for adults and 2{\%} for children. However, the IGF-I levels of both the mothers and fathers were not significantly different from that of the control population. The serum IGF-II levels of the GHRD patients were approximately 20{\%} of control values for adults and 12{\%} for the children. The IGF-II levels of the mothers were reduced, but were not significantly different from that of the control population. However, IGF-II levels of the fathers were significantly lower than those of controls (64{\%} of control male levels). WLB analysis of serum IGFBP levels of the affected subjects demonstrated increased IGFBP-2 and decreased IGFBP-3, suggesting an inverse relationship between these IGFBPs. The GHRD patients who had the lowest serum IGFBP-3 levels (as measured by WLB) demonstrated a serum protease activity that could proteolyze 125I-IGFBP-3. GHRD patients who had higher serum IGFBP-3 levels lacked this serum protease activity. There were no differences in the serum IGFBP profiles of the mothers or the fathers for either IGFBP-2 or IGFBP-3, and serum from both groups lacked the ability to significantly proteolyze 125I-IGFBP-S. While GHRD patients had very low levels of serum GHBP, some patients did have measurable GHBP levels. The mean GHBP levels of the mothers (76{\%} of control females) and father (64{\%} of control males), while reduced, did not significantly differ from those of controls. Thus, while serum IGF-II and GHBP levels were somewhat reduced in the parents of the GHRD patients, they do not appear to provide a reliable biochemical marker for heterozygosity of the defective gene.",
author = "Fielder, {Paul J.} and Jaime Guevara-Aguirre and Rosenbloom, {Arlan L.} and Lena Carlsson and Hintz, {Raymond L.} and Rosenfeld, {Ronald (Ron)}",
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T1 - Expression of serum insulin-like growth factors, insulin-like growth factor-binding proteins, and the growth hormone-binding protein in heterozygote relatives of Ecuadorian growth hormone receptor deficient patients

AU - Fielder, Paul J.

AU - Guevara-Aguirre, Jaime

AU - Rosenbloom, Arlan L.

AU - Carlsson, Lena

AU - Hintz, Raymond L.

AU - Rosenfeld, Ronald (Ron)

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N2 - Recently, an isolated population of apparent GH-receptor deficient (GHRD) patients has been identified in the Loja province of southern Ecuador. These individuals presented many of the physical and biochemical phenotypes characteristic of Laron-Syndrome and are believed to have a defect in the GH-receptor gene. In this study, we have compared the biochemical phenotypes between the affected individuals and their parents, considered to be obligate heterozygotes for the disorder. Serum GH, insulin-like growth factor I and II (IGF-I and IGF-II) levels were measured by RIA Insulin-like growth factor binding proteins. (IGFBPs) were measured by Western ligand blotting (WLB) of serum samples, following separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and relative quantitation of serum IGFBPs was performed with a scanning laser densitometer. Serum GH-binding protein (GHBP) levels were measured with a ligand-mediated immunofunctional assay using a monoclonal antibody raised against the GHBP. These values were then compared to values obtained from normal, sex-matched adult Ecuadorian controls, to determine if the above parameters were abnormal in the heterozygotes. The serum IGF-I levels of the GHRD patients were less than 13% of control values for adults and 2% for children. However, the IGF-I levels of both the mothers and fathers were not significantly different from that of the control population. The serum IGF-II levels of the GHRD patients were approximately 20% of control values for adults and 12% for the children. The IGF-II levels of the mothers were reduced, but were not significantly different from that of the control population. However, IGF-II levels of the fathers were significantly lower than those of controls (64% of control male levels). WLB analysis of serum IGFBP levels of the affected subjects demonstrated increased IGFBP-2 and decreased IGFBP-3, suggesting an inverse relationship between these IGFBPs. The GHRD patients who had the lowest serum IGFBP-3 levels (as measured by WLB) demonstrated a serum protease activity that could proteolyze 125I-IGFBP-3. GHRD patients who had higher serum IGFBP-3 levels lacked this serum protease activity. There were no differences in the serum IGFBP profiles of the mothers or the fathers for either IGFBP-2 or IGFBP-3, and serum from both groups lacked the ability to significantly proteolyze 125I-IGFBP-S. While GHRD patients had very low levels of serum GHBP, some patients did have measurable GHBP levels. The mean GHBP levels of the mothers (76% of control females) and father (64% of control males), while reduced, did not significantly differ from those of controls. Thus, while serum IGF-II and GHBP levels were somewhat reduced in the parents of the GHRD patients, they do not appear to provide a reliable biochemical marker for heterozygosity of the defective gene.

AB - Recently, an isolated population of apparent GH-receptor deficient (GHRD) patients has been identified in the Loja province of southern Ecuador. These individuals presented many of the physical and biochemical phenotypes characteristic of Laron-Syndrome and are believed to have a defect in the GH-receptor gene. In this study, we have compared the biochemical phenotypes between the affected individuals and their parents, considered to be obligate heterozygotes for the disorder. Serum GH, insulin-like growth factor I and II (IGF-I and IGF-II) levels were measured by RIA Insulin-like growth factor binding proteins. (IGFBPs) were measured by Western ligand blotting (WLB) of serum samples, following separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and relative quantitation of serum IGFBPs was performed with a scanning laser densitometer. Serum GH-binding protein (GHBP) levels were measured with a ligand-mediated immunofunctional assay using a monoclonal antibody raised against the GHBP. These values were then compared to values obtained from normal, sex-matched adult Ecuadorian controls, to determine if the above parameters were abnormal in the heterozygotes. The serum IGF-I levels of the GHRD patients were less than 13% of control values for adults and 2% for children. However, the IGF-I levels of both the mothers and fathers were not significantly different from that of the control population. The serum IGF-II levels of the GHRD patients were approximately 20% of control values for adults and 12% for the children. The IGF-II levels of the mothers were reduced, but were not significantly different from that of the control population. However, IGF-II levels of the fathers were significantly lower than those of controls (64% of control male levels). WLB analysis of serum IGFBP levels of the affected subjects demonstrated increased IGFBP-2 and decreased IGFBP-3, suggesting an inverse relationship between these IGFBPs. The GHRD patients who had the lowest serum IGFBP-3 levels (as measured by WLB) demonstrated a serum protease activity that could proteolyze 125I-IGFBP-3. GHRD patients who had higher serum IGFBP-3 levels lacked this serum protease activity. There were no differences in the serum IGFBP profiles of the mothers or the fathers for either IGFBP-2 or IGFBP-3, and serum from both groups lacked the ability to significantly proteolyze 125I-IGFBP-S. While GHRD patients had very low levels of serum GHBP, some patients did have measurable GHBP levels. The mean GHBP levels of the mothers (76% of control females) and father (64% of control males), while reduced, did not significantly differ from those of controls. Thus, while serum IGF-II and GHBP levels were somewhat reduced in the parents of the GHRD patients, they do not appear to provide a reliable biochemical marker for heterozygosity of the defective gene.

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