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Department of Pediatrics, Oregon Health & Sciences University (V.H., B.L., E.M.K., K.L.P., R.G.R.), Portland, Oregon 97239; Faculty of Medicine, Department of Pediatric Endocrinology, Ankara University (P.A., G.O., M.B.), Ankara, Turkey; Department of Pediatrics, Stanford University (R.G.R.), Palo Alto, California 94304; and Lucile Packard Foundation for Children’s Health (R.G.R.), Palo Alto, California 94304
Address all correspondence and requests for reprints to: Dr. Vivian Hwa, Department of Pediatrics, NRC5, Oregon Health & Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: hwav{at}ohsu.edu.
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Abstract |
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Objective: We investigated the GH-IGF-I axis in a young female GHI subject who presented with a height of 114 cm (–7.8 SD score) at age 16.4 yr.
Patient: The subject, from a consanguineous pedigree, had circulating levels of GH and GH-binding protein that were normal to elevated, whereas IGF-I (7.2 ng/ml; normal, 242–600), IGF-binding protein-3 (543 ng/ml; normal, 2500–4800), and acid-labile subunit (1.22 µg/ml; normal, 5.6–16) levels were abnormally low and failed to increase during an IGF-I generation test.
Design: Dermal fibroblast cultures were established with the consent of the patient and family. Immunoblot analysis of cell lysates and DNA sequencing of her signal transducer and activator of transcription 5b (STAT5b), a critical intermediate of the GH-IGF-I axis, were performed.
Results: Sequencing of the STAT5b gene revealed a novel homozygous insertion of a single nucleotide in exon 10. The insertion resulted in a frame shift, leading to early protein termination and consequent lack of immunodetectable STAT5b protein.
Conclusion: The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.
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Introduction |
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TopAbstractIntroductionCase ReportMaterials and MethodsResultsDiscussionReferences |
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GHI in the presence of normal GHR, in contrast to classical GHI, has remained largely uninvestigated. The molecular basis has been determined in only a few cases, including a report of a deletion in the IGF-I gene (11). Mutations in the IGF-I receptor gene have been reported to result in resistance to IGF-I action with partial resistance to GH (12), although in this situation, serum IGF-I concentrations typically are elevated. More recently, a case of GHI was found to be associated with a mutation in the gene encoding the signal transducer and activator of transcription 5b (STAT5b) (13), an intermediate critical in GHR and other cytokine receptor signaling. The consequence of the STAT5b mutation was GH-induced (13) and interferon-
(IFN-)-induced (14) dysregulation of IGF-I expression. Nonclassical GHI phenotypes, thus, may clearly result from abnormalities downstream of GHR.
The GHR signaling cascade is initiated upon interaction of GH with its receptor, which recruits and activates cytosolic Janus kinase 2 (JAK2). JAK2 undergoes autophosphorylation and simultaneously phosphorylates tyrosines on GHR. The phosphotyrosines on the receptor act as docking sites for multiple adaptors of the STAT, phosphatidylinositol 3-kinase, and MAPK signaling pathways. The STATs are a family of cytosolic latent transcription factors composed of six modular protein domains. Through their Src homology 2 domain (SH2), STATs dock to phosphotyrosines on activated receptors, including GHR, and are subsequently phosphorylated by JAK2 on a single tyrosine located distal to SH2. Once phosphorylated, the STATs dissociate from the receptor, homo- or heterodimerize, and translocate to the nucleus, where the activated STAT dimers bind DNA and function as transcription factors. Targeted disruption studies in rodents have indicated that STAT5b, of the seven mammalian STATs, is required for sexual dimorphic body growth, with male STAT5b–/– mice reduced to the size of female mice. No differences in growth rates, however, were observed between normal and STAT5b–/– female mice (15, 16). Serum IGF-I levels, furthermore, were reduced by only 30–50%. It was, therefore, striking that the first identification of a homozygous autosomal recessive missense STAT5b mutation in humans was reported in a female subject, who demonstrated extreme short stature (–7.5 SD) and had serum IGF-I levels less than 15% of normal (13). In this study we report the absence of STAT5b in another young female patient, who presented with growth characteristics identical with those of the previously reported patient. Together, these two cases convincingly implicate STAT5b mutations as potential etiologies of the GHI syndrome and point to STAT5b playing an important role in normal postnatal human growth.
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Case Report |
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The subject was first referred to an endocrine center at 7.8 yr of age, when her height was 94 cm and her weight was 10.5 kg, both significantly below the third percentile (Fig. 1A
). Her bone age was determined to be 4 yr, which was 3.8 yr retarded relative to her chronological age. Magnetic resonance imaging indicated that her pituitary size was normal, and endocrine analysis of spontaneous overnight GH secretion indicated normal to high concentrations of GH, with integrated levels of 14.2 ng/ml. A course of recombinant GH therapy was initiated, but was terminated after 3 months at the request of the parents. Growth continued to be severely retarded (Fig. 1A), and an IGF-I generation test performed at 15 yr of age indicated extremely low serum concentrations of IGF-I (<5 ng/ml, by RIA), which remained abnormally low after 4 d of GH treatment. At 16 yr of age, the subject was –7.8 SD for height, with no signs of pubertal onset. Evaluations of circulating GH-binding protein (GHBP) indicated that the GHBP level was normal (1232 pmol/liter; normal range, 431-1892), but circulating IGF-I (7 ng/ml; normal, 242–660), IGF-binding protein-3 (IGFBP-3; 543 ng/ml; normal, 2500–4800), and acid-labile subunit (ALS; 1.2 µg/ml; normal, 5.6–16) were markedly low.
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). Immunological evaluation indicated hypergammaglobulinemia at 7.8 yr of age, which was normalized by age 15 yr. Gross T cells, B cells, and natural killer cells were within the normal range when evaluated at age 15 yr, and the lymphoproliferative response was also determined to be normal. |
Materials and Methods |
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Serum assays
Serum samples from the patient and family were obtained with consent and in compliance with the institutional review board (Oregon Health & Sciences University, Portland, OR; and Ankara University School of Medicine, Ankara, Turkey). Samples were analyzed for IGF-I and IGFBP-3 levels by means of immunoradiometric assays (Diagnostic Systems Laboratories, Webster, TX). ALS and GHBP were measured with ELISAs (Diagnostic Systems Laboratories).
Cell culture
Primary fibroblast cultures were established from skin biopsies taken from the patient (BF cells) with consent and in compliance with the institutional review boards of both Oregon Health and Sciences University and Ankara University School of Medicine. Normal human dermal fibroblasts (CF cells) and dermal fibroblasts carrying the missense STAT5b mutation (PF cells) have been described previously (13). Cell cultures were maintained in 
-MEM Earle’s (Cellgro, Mediatech, Herndon, VA) supplemented with 20% fetal bovine serum (Invitrogen Life Technologies, Inc., Grand Island, NY) at 37 C in 5% CO2. COS-7 cells (American Type Culture Collection, Manassas, VA) were maintained in DMEM supplemented with 10% fetal bovine serum.
Western immunoblotting
Cells were solubilized in RIPA lysis buffer (1x PBS, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, 10 mg/ml phenylmethylsulfonylfluoride, and 100 mM sodium orthovanadate) supplemented with complete protease inhibitor cocktail (Roche, Mannheim, Germany). The total protein concentration was determined using the DC protein assay (Bio-Rad Laboratories, Hercules, CA). Equal quantities of protein were solubilized in reducing and denaturing sodium dodecyl sulfate sample buffer [0.5 mol/liter Tris (pH 6.8), 2% sodium dodecyl sulfate, 10% glycerol, 5% ß-mercaptoethanol, 1 mM dithiothreitol, and 0.003% bromphenol blue] and boiled for 5 min. Samples were electrophoresed on 7% or 12% sodium dodecyl sulfate-polyacrylamide gels and electroblotted onto nitrocellulose, and membranes blocked with 4% milk/Tris-buffered saline/0.1% Tween 20) for 1 h at room temperature. For Western immunoblot analysis, the indicated primary and secondary antibodies were applied as recommended by the manufacturers. Proteins of interest were detected with ECL chemiluminescence reagents, according to the manufacturer’s protocol (PerkinElmer Life Sciences).
Genomic DNA and cDNA
Genomic DNA was obtained from primary fibroblast cultures employing the Puregene DNA purification system (Gentra Systems, Minneapolis, MN). Panels of normal genomic DNAs were also purchased from Coriell Cell Repositories (Camden, NJ). Primers for PCR amplification of exons 10–12 were: forward, 10-f (intron 9), 5'-gggtttggagctggtctctct-3'; and reverse, 12-r (intron 12), 5'-gagattcatgacaccggcattgatttt-3'. For sequencing of exon 10, primer 10-f and primer 5b12-r (exon 11) were employed (5'-accgactctgccccacgac-3'). Total RNA was extracted from primary fibroblast cells employing the RNeasy silica membrane purification system (QIAGEN, Valencia, CA). Total RNA was quantified by spectrophotometer and used in RT-PCR amplifications (see below).
RT-PCR
RT reactions were performed with 1 mg total RNA, oligo(deoxythymidine)16 (Integrated DNA Technologies, Coralville, IA), and SuperScript II ribonuclease H– reverse transcriptase (Invitrogen Life Technologies, Inc., Carlsbad, CA). Primers for amplification of STAT5b and 18S (Integrated DNA Technologies) were previously described (13, 14). PCR amplification was performed using Taq polymerase (Promega Corp., Madison, WI) according to the manufacturer’s protocol; cycling conditions were previously described (13, 14). PCR products were visualized by standard agarose gel electrophoresis. Primers employed for sequencing STAT5b cDNA were described previously (13, 14).
Generation of recombinant mutant N-FLAG-STAT5b:1191insG
For reconstitution experiments, the insertion mutant was generated by recombinant methodology, employing the QuikChange mutagenesis kit (Stratagene, La Jolla, CA), with N-terminally FLAG-tagged STAT5b cDNA (F-STAT5b) (14) as template. The primers were: forward, 5'-gattacagtggcgagatcttggaacaactgctgcgtcatgga-3'; and reverse, 5'-tccatgacgcagcagttgttccaagatctcgccactgtaatc-3'. The inserted nucleotide is underlined. Sequencing of the resulting mutated STAT5b cDNA confirmed correct insertion of the extra nucleotide.
Transfection experiments
COS-7 cells were grown to approximately 50% confluence and were transiently transfected with vector, pcDNA3.1, or vector carrying F-STAT5b, F-STAT5b:A630P, or F-STAT5b:1191insG using TranskIT-LT1 (Mirus, Madison, WI). After transfection for 24 h, total RNA and cell lysates were collected, and the expression of F-STAT5b variants was analyzed by RT-PCR and by Western immunoblot.
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Results |
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The young female subject presented with severe growth retardation (Fig. 1) associated with elevated levels of circulating GH. Circulating GHBP was within the normal range (Table 1), whereas IGF-I, IGFBP-3, and ALS levels were abnormally low. In contrast, the parents and two brothers of the patient showed normal levels of all four components (Table 1). An IGF-I generation test (17), in which the subject was treated with human recombinant GH (0.1 mg/kg·d) for 4 consecutive days, confirmed the lack of responsiveness to GH, with the markedly low baseline IGF-I (<5 ng/ml, as determined by RIA) remaining abnormally low after 4 d of GH treatment. Together, the results were consistent with severe GHI.
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GHI can be the result of abnormalities of GHR or of defective post-GHR signaling. In our subject, severe growth retardation combined with recurrent pulmonary infections was reminiscent of observations made in a previously described GHI subject identified as carrying a STAT5b missense mutation (13). In the reported case, the STAT5b missense mutation generated a protein (STAT5b:A630P) that was poorly detectable by immunoblot analysis. We, therefore, screened for the expression of STAT5b protein in the present subject by immunoblot analysis of cell lysates derived from the subject’s primary dermal fibroblasts (BF cells). Employing a highly specific monoclonal antibody against STAT5b, STAT5b was readily immunodetected in cell lysates from two normal dermal fibroblast cell lines (Fig. 2, CF1 and CF3). Mutant STAT5b:A630P in cell lysates from PF cells (13) was, as reported previously, poorly immunodetected. Strikingly, even less intact STAT5b protein was detected in cell lysates from BF cells. In contrast, the closely related STAT5a protein was readily identified by immunoblot analysis in BF cells, at levels comparable to those found in CF cells. Identical results were obtained when an anti-STAT5a/b antibody generated against a peptide in the DBD domain was employed (data not shown). Clearly, intact STAT5b appeared to be very poorly expressed, if at all, in the subject.
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To determine the genetic basis for the apparent lack of immunodetectable STAT5b, STAT5b cDNA was RT-PCR amplified from BF cells, and the cDNA was sequenced. The results revealed a novel homozygous insertion of a single nucleotide at position 1191 of the STAT5b open reading frame (designated 1191insG; Fig. 3A). The insertion not only changed asparagine at amino acid residue 398 to glutamic acid (N398E), but also generated a frame shift leading to the introduction of a stop codon 15 amino acids downstream from N398 (schematically presented in Fig. 3B). The mutation was confirmed at the gene level, with the homozygous nucleotide insertion located in exon 10, which encodes the portion of the DBD segment encompassing D391 to S420. No polymorphisms or heterozygosity in exon 10 were detected in DNA sequences of the STAT5b gene from 50 normal subjects.
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The consequence of the frame-shift mutation is early termination of STAT5b protein synthesis, with loss of the C-terminal half of the protein (Fig. 3B). To determine whether the predicted truncated STAT5b protein was stably expressed, immunoblot analysis of total cell lysates from BF and CF cells was performed employing anti-STAT5b antibody generated against the DBD region. The antibody should recognize the truncated protein, if stable, because the epitope (residues 371–389) is proximal to the site of insertion. As shown in Fig. 4A, although STAT5b was readily detected in normal CF cells, neither intact nor STAT5b variants of lower molecular weight were immunodetected in the patient’s cells (BF).
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). The transcriptional expression of each input plasmid was equivalent for each transfection. |
Discussion |
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TopAbstractIntroductionCase ReportMaterials and MethodsResultsDiscussionReferences |
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The novel frame-shift mutation in STAT5b described in the present case generates a truncated mutant STAT5b protein that lacks the C-terminal half of the protein, encompassing part of the DBD, the SH2 (including the critical Y699), and transactivation domain regions. The resultant severely truncated protein, retaining intact N-terminal domain, and coiled-coil domain, might still have been anticipated to exert some biological effects, because it was recently suggested that STAT proteins, before activation by cytokines, are capable of forming stable homodimers through specific interactions involving the N-terminal domain (18). However, the lack of immunodetectable truncated STAT5b, even when overexpressed in reconstitution systems, suggests rapid degradation of the mutant STAT5b protein. STAT5b expression is, therefore, essentially ablated in the subject under study.
The consequence of the homozygous missense or frame-shift STAT5b mutations to the postnatal growth of the two recently identified patients was striking, with severe postnatal growth failure and growth profiles that were essentially superimposable (Fig. 5). Furthermore, these growth characteristics are virtually identical with those observed in GHR deficiency in both Israel and Ecuador (19, 20) (Fig. 5). These similar growth patterns together with serum concentrations of IGF-I, IGFBP-3, and ALS that are consistent with those observed in patients with severe homozygous mutations of GHR argue that the overwhelming majority (if not all) of GH stimulation of IGF-I and IGFBP-3 production is mediated through the JAK-STAT system, with minimal involvement of the other GH signaling pathways, such as the MAPK/ERK and phosphatidylinositol 3-kinase pathways. Consistent with this hypothesis, isolated failure of GH-induced STAT5b signaling was recently described in two GHI cases in which novel C-terminal GHR deletions resulted in normal ERK2 and STAT3 signaling, but defective activation of STAT5b (9, 10).
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Interestingly, the postnatal growth characteristics of patients with mutations of GHR and STAT5b are also comparable with those observed in the one identified patient with homozygosity for an IGF-I gene deletion (Fig. 5). Although this patient was male, in contrast with the two patients with STAT5b mutations, comparisons may still be made, because normal prepubertal growth of males and females is virtually identical. More importantly, the patient with the IGF-I gene deletion was characterized by severe intrauterine growth retardation (birth weight, –3.9 SD; birth length, –5.4 SD), whereas the two patients with STAT5b mutations as well as patients with GHR deficiency had near-normal size at birth. Despite these differences in birth size, the postnatal growth curves of all three conditions (i.e. GHR mutations, STAT5b mutations, and IGF-I mutations) are essentially indistinguishable (Fig. 5). Although care must be taken in extrapolations based on a handful of cases, these observations suggest that, at least in humans, the majority of skeletal growth-promoting actions of GH are mediated through the GHR-JAK2-STAT5b-IGF-I pathway (Fig. 6). Simultaneously, it is clear that other factors can impact IGF-I production, such as IFN-, acting through the STAT5b pathway (14), and sex steroids, acting either directly or by stimulating GH secretion. Nevertheless, clinical observations would suggest that the overwhelming majority of IGF-dependent postnatal growth is mediated through the GH-GHR-STAT5b pathway. Although these observations do not totally contradict findings in mice (21, 23), in which studies have suggested an additive effect when both the GHR and IGF-I genes are inactivated, they serve to underscore the central role of the GH-GHR-STAT5b-IGF-I pathway in postnatal growth.
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Unlike its central importance in GH-IGF-I-mediated growth, the specific role(s) of STAT5b in normal immunity is less clear, although many cytokines, such as IL-2, IL-7, IL-21, and IFNs, can activate STAT5b. We have demonstrated recently that the cytokine IFN-, like GH, could not activate mutant STAT-5b:A630P, resulting in markedly reduced expression of the IGF-I gene (14). It is not clear, however, that IGF-I deficiency alone can account for the immune deficiencies in both GHI patients, because, as noted above, other forms of GH deficiency and GHI, with similarly low serum concentrations of IGF-I, are not immunologically compromised. It is more likely that cytokines important for cellular immunity, such as IFN-, require STAT-5b for efficient regulation of multiple genes, including IGF-I. In conclusion, the complex clinical phenotype presented by the two patients with mutations of the STAT5b gene supports a central role for STAT5b in both GH and cytokine actions.
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Footnotes |
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First Published Online April 12, 2005
Abbreviations: ALS, Acid-labile subunit; DBD, DNA-binding domain; GHBP, GH-binding protein; GHI, GH insensitivity; GHR, GH receptor; IFN-, interferon-; IGFBP-3, IGF-binding protein-3; JAK2, Janus kinase 2; SH2, Src homology 2 domain; STAT5b, signal transducer and activator of transcription 5b.
Received March 8, 2005.
Accepted April 5, 2005.
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References |
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(IFN-) requires Stat-5b. J Biol Chem 279:2728–2736This article has been cited by other articles:
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