Signal transduction defects in growth hormone insensitivity

Growth hormone (GH) insensitivity is a heterogeneous condition that can result from mutations within the GH receptor (GHR) and that can be inherited as both an autosomal recessive and a dominant trait. However, evidence from a small number of growth hormone binding protein (GHBP)-positive families indicates that their GH insensitivity is independent of GHR mutations. Two of these families appear to have distinct abnormalities in GH signal transduction. Studies suggest that one family (classic Laron syndrome phenotype; designated family H) have a signalling defect close to the GHR, preventing activation of both the STAT and MAPK pathways, whereas the other family (less marked phenotype; family M) have a defect in activating MAPK but not the STAT pathway. The children studied here are specifically insensitive to GH and their defect must be exclusive to this signalling system. Thus, families with GHBP-positive GH insensitivity without GHR mutations are likely to be important models in which to study the specificity of GH signal transduction and the relationship between GH insensitive phenotype and signalling defect.     

Truncated growth hormone receptor isoforms

Ross RJM. Truncated growth hormone receptor isoforms. Acta Pædiatr 1999; Suppl 428: 164–6. Stockholm. ISSN 0803–5326
Truncated forms of the growth hormone receptor (GHR) that lack the majority of the cytoplasmic domain have been identified in a number of human tissues. In vitro , these truncated receptors act as dominant-negative inhibitors of the growth hormone (GH) signal and also generate large amounts of growth hormone binding protein (GHBP). Mutations that lead to high levels of expression of the truncated GHR are associated with short stature and GH insensitivity. Thus, truncated GHRs may be important as a physiological regulator of GH signalling in addition to providing a mechanism for the production of GHBR □ Cirrhosis, growth hormone, growth hormone insensitivity, growth hormone receptor, growth hormone resistance, truncated growth hormone receptor     

Novel mutation involving the translation initiation codon of the growth hormone receptor gene (GHR) in a patient with Laron syndrome

Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS) is an autosomal recessive disease due to molecular defects in the GH receptor gene (GHR). Most of the identified mutations are located on the extracelular domain of the receptor. We studied the GHR gene in a patient with LS and found a homozygous missense mutation in exon 2. The novel mutation is an A-->T transversion (ATG -->TTG) that abolishes the translation initiation codon of the GHR gene. This mutation is expected to prevent the translation of the protein. We present clinical, biochemical and molecular evidence of Laron syndrome as the result of a mutation (ATG-->TTG) in the codon for the initial methionine of the GHR gene.     

Novel splice site mutation in the growth hormone receptor gene in Turkish patients with Laron-type dwarfism

Growth hormone (GH) is involved in growth, and fat and carbohydrate metabolism. Interaction of GH with the GH receptor (GHR) is necessary for systemic and local production of insulin-like growth factor-I (IGF-I) which mediates GH actions. Mutations in the GHR cause severe postnatal growth failure; the disorder is an autosomal recessive genetic disease resulting in GH insensitivity, called Laron syndrome. It is characterized by dwarfism with elevated serum GH and low levels of IGF-I. We analyzed the GHR gene for mutations and polymorphisms in eight patients with Laron-type dwarfism from six families. We found three missense mutations (S40L, V125A, I526L), one nonsense mutation (W157X), and one splice site mutation in the extracellular domain of GHR. Furthermore, G168G and exon 3 deletion polymorphisms were detected in patients with Laron syndrome. The splice site mutation, which is a novel mutation, was located at the donor splice site of exon 2/ intron 2 within GHR. Although this mutation changed the highly conserved donor splice site consensus sequence GT to GGT by insertion of a G residue, the intron splicing between exon 2 and exon 3 was detected in the patient. These results imply that the splicing occurs arthe GT site in intron 2, leaving the extra inserted G residue at the end of exon 2, thus changing the open reading frame of GHR resulting in a premature termination codon in exon 3.     

Partial growth hormone insensitivity - idiopathic short stature is not always idiopathic

Saenger P. Partial growth hormone insensitivity - idiopathic short stature is not always idiopathic. Acta Pædiatr 1999; Suppl 428: 194–8. Stockholm. ISSN 0803–5326
Heterozygous growth hormone receptor (GHR) gene defects are not a common cause of idiopathic short stature. Although some of these GHR mutations may result in relative insensitivity to growth hormone (GH) in other studies, obligate heterozygotes did not present any clinical manifestations. Although patients with GH insensitivity and elevated GH binding protein (GHBP) levels have been described, it may be a reasonable approach to screen children who have growth failure, low levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, and low levels of GHBP. Whether the sensitivity of this screening approach can be increased by administering pharmacological doses of GH for a few days and measuring the resultant increase in serum IGF-I concentration remains to be determined by ongoing studies. □ Growth hormone insensitivity, growth hormone receptor, short stature     

Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome

Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.     

A novel mutation of the growth hormone receptor gene (GHR) in a Chinese girl with Laron syndrome

Laron syndrome, also known as growth hormone insensitivity syndrome (GHIS), is an autosomal recessive genetic disorder associated with severe postnatal growth failure, and normal and/or elevated growth hormone. This disease is frequently caused by a point mutation in the growth hormone receptor gene (GHR). Here, we identified a novel homozygous substitution mutation (E42K: GAG-->AAG at codon 42 cDNA) of the GHR gene in a Chinese girl with Laron syndrome. This mutation was predicted to impair the GHR binding affinity to human growth hormone (hGH), and was responsible for low levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, and GH binding protein (GHBP) in serum.     

Identification of a novel mutation in the human growth hormone receptor gene (GHR) in a patient with Laron syndrome

Deletions and mutations in the growth hormone receptor (GHR) gene are the underlying etiology of Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS), an autosomal recessive disease. Most patients are distributed in or originate from Mediterranean and Middle-Eastern countries. Sixty mutations have been described so far. We report a novel mutation in the GHR gene in a patient with LS. Genomic DNA sequencing of exon 5 revealed a TT insertion at nucleotide 422 after codon 122. The insertion resulted in a frameshift introducing a premature termination codon that led to a truncated receptor. We present clinical, biochemical and molecular evidence of LS as the result of this homozygous insertion.     

Relationship between phenotype and genotype in growth hormone insensitivity syndrome

Woods KA, Clark AJL, Amselem S, Savage MO. Relationship between phenotype and genotype in growth hormone insensitivity syndrome. Acta Pædiatr 1999; Suppl 428: 158–62. Stockholm. ISSN 0803–5326
Growth hormone insensitivity syndrome (GHIS) of genetic origin is associated with many different mutations of the growth hormone receptor (GHR) gene and a recently described genetic defect of the insulin-like growth factor I (IGF-I) gene. Phenotypic and biochemical features were examined in a cohort of 82 patients with GHIS from 23 countries. The mean age of these patients was 8.3 years, their mean height SDS was -6.09 and their median IGF-binding protein-3 (IGFBP-3) SDS was -8.5. In total, 19 of the 82 patients (23%) were growth hormone-binding protein (GHBP)-positive (> 10%). The mean heights in GHBP-negative and GHBP-positive patients were -6.45 SDS and -4.89 SDS, respectively ( p < 0.001). Sixteen different GHR gene mutations were identified in 27 patients with GHIS. All of these patients had homozygous mutations, except one who had a compound heterozygous mutation. There was no relationship between the type or site within the GHR gene of the mutation and the height SDS or IGFBP-3 SDS of the patients. GHIS is associated with a wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene alone. Other genes or environmental factors must contribute to the control of growth in patients with GHIS. □ Growth hormone, growth hormone insensitivity, growth hormone receptor gene     

Truncated growth hormone receptor isoforms

Truncated forms of the growth hormone receptor (GHR) that lack the majority of the cytoplasmic domain have been identified in a number of human tissues. In vitro, these truncated receptors act as dominant-negative inhibitors of the growth hormone (GH) signal and also generate large amounts of growth hormone binding protein (GHBP). Mutations that lead to high levels of expression of the truncated GHR are associated with short stature and GH insensitivity. Thus, truncated GHRs may be important as a physiological regulator of GH signalling in addition to providing a mechanism for the production of GHBP.     

一个Laron 综合征家系患者临床特点和生长激素受体基因突变分析

Laron 综合征是一种常染色体隐性遗传病,生长激素受体（GHR）基因缺陷是导致Laron 综合征的主要病因。Laron 综合征主要临床特征为生后严重的生长落后伴特殊面容,血生化特点为高生长激素(GH)、低胰岛素样生长因子- (IGF-I) 和低胰岛素样生长因子结合蛋白- (IGFBP-3)。该研究报道一家系2例Laron 综合征患者的临床特点及GHR基因突变。这两个病人为同胞姐弟。弟弟8岁,身高80.0 cm (-8.2 SDS),姐姐11岁,身高96.6 cm (-6.8 SDS)。他们出生体重和身长无特殊,自生后出现生长落后,身高明显落后于同龄正常儿童,并均呈现了典型Laron 综合征外貌特征：身材矮、肥胖、前额突出、大眼睛、塌鼻梁、头发稀软。这两个病人空腹血清GH值均明显高于正常儿童,空腹血清IGF-I明显低于同年龄同性别正常儿童,血浆IGFBP-3和生长激素结合蛋白（GHBP）低于检测线。其中1例（8岁男孩）胰岛素和可乐定刺激后GH峰值大于350 ng/mL,给予重组人生长激素治疗1年,身高由治疗前的80.0 cm 增加至83.3 cm。GHR基因序列测定结果显示2例患者均存在外显子4上第65位氨基酸的纯合突变S65H(TCA → CCA),为新发现的突变。Laron 综合征患者存在特殊的面貌特征,结合血GH、IGF-I、IGFBP-3和GHBP测定可以明确诊断。GHR基因外显子4上S65H突变可能是这两位Laron 综合征患者的致病原因。［中国当代儿科杂志,2007,9（4）：335-338］     

生长激素受体基因突变与非生长激素缺乏性矮身材的相关研究

目的了解生长激素受体（GHR）基因突变与非生长激素缺乏性矮小的相关性,以及GHR基因突变患儿的临床特点。方法（1）选择47例（男33例,女14例,年龄2—16岁）非生长激素缺乏而又显著矮小的患儿作为研究对象;80例身高正常的儿童（男49例,女31例,年龄1—17岁）作为对照组。（2）应用PCR-SSCP和基因测序技术检测GHR突变。（3）通过家系成员和正常对照人群的基因分析以及氨基酸同源序列分析等,推测突变基因的性质。结果（1）在47例矮小患儿中有5例、4种不同的GHR基因突变：H56R、G148E、IVS6-30,-31CA〉TG和IVS8＋10G〉C。5例患儿均为杂合突变,杂合突变个体的检出频率为10．6％（5／47）。（2）对照组的基因分析显示这些突变非多态性改变,初步认为H56R和G148E突变可能对蛋白功能产生影响。（3）确定了1种多态性突变：G168G（GGA〉GGG）。该位点基因频率的分布在矮小儿童组和正常对照组之间的差异无统计学意义,但与西方白种人之间的差异有统计学意义。提示该突变可能是单核苷酸多态性改变,与身高没有相关关系。但该位点的等位基因存在人种的差异。结论非生长激素缺乏性矮身材患儿存在GHR基因杂合突变。     

Partial growth hormone insensitivity

Partial growth hormone (GH) insensitivity can be defined as the clinical and biochemical features of IGF-I deficiency without GH deficiency and in the absence of the dysmorphic features of Laron syndrome. There is good evidence that this form of GH insensitivity exists, both in the context of severe GH resistance, and also in some patients with idiopathic short stature. The series of GH insensitivity patients in the European study shows a spectrum of clinical and biological defects, with several patients at the milder end of the spectrum having normal facies. The report of the presence of heterozygous mutations of the GH receptor in patients with idiopathic short stature has been confirmed by documentation of dominantly inherited mutations in familial short stature. Molecular screening in our unit of a group of 31 children with idiopathic short stature and normal GHBP, failed to identify mutations of the intracellular domain of the GH receptor. Consequently, although partial GH insensitivity is a proven entity, the clinical and biochemical identification of patients with GH resistance should precede molecular analysis. The analysis of individual patients and their families is more likely to reveal mutations, rather than a strategy of blanket molecular screening.     

New growth hormone receptor exon 9 mutation causes genetic short stature

Ayling RM, Ross RJM, Towner P, Von Laue S, Finidori J, Moutoussamy S, Buchanan CR, Clayton PE, Norman MR. Acta Pa; diatr 1999; Suppl 428: 168–72. Stockholm. ISSN 0803–5326.
A novel form of congenital growth hormone insensitivity syndrome (GHIS), which lacks the classic phenotype associated with this condition, is described. Dominant inheritance is shown to result from a heterozygous 876–1 G to C transversion of the 3' splice acceptor site preceding exon 9 in the growth hormone receptor (GHR) gene. The result of this mutation is a severely truncated cytoplasmic domain of the GHR, which is incapable of transmitting a signal. The mutant receptor is shown to form a heterodimer with the wild-type GHR, the activity of which is inhibited in a dominant-negative manner. □ Dominant-negative mutation, growth hormone receptor     

Partial growth hormone insensitivity--idiopathic short stature is not always idiopathic

Heterozygous growth hormone receptor (GHR) gene defects are not a common cause of idiopathic short stature. Although some of these GHR mutations may result in relative insensitivity to growth hormone (GH) in other studies, obligate heterozygotes did not present any clinical manifestations. Although patients with GH insensitivity and elevated GH binding protein (GHBP) levels have been described, it may be a reasonable approach to screen children who have growth failure, low levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, and low levels of GHBP. Whether the sensitivity of this screening approach can be increased by administering pharmacological doses of GH for a few days and measuring the resultant increase in serum IGF-I concentration remains to be determined by ongoing studies.     

Laron综合征家系患者生长激素受体基因突变分析

目的研究Laron综合征患者的临床特点及生长激素受体（GHR）的基因突变。方法对一家系中2例表现为身材明显落后的患儿进行研究，分别进行体格测量和GH-IGF—I轴功能测定。提取外周血白细胞基因组DNA，运用聚合酶链式反应（PCR）扩增GHR基因第2～9外显子及其两侧的侧翼序列，直接进行测序，将所测结果与正常人GHR基因序列进行对比，确定突变位点和突变类型。对突变基因均经2次测定证实。结果2例患儿自出生后身长明显落后于同龄儿童，呈现Laron综合征的独特面貌，空腹血清GH值均明显高于正常儿童。空腹血清IGF-I明显低于同年龄同性别正常儿童。血浆IGFBP-3和GHBP低于检测线。GHR基因序列测定结果显示2例患儿均存在外显子4上第65为氨基酸的纯合突变S65H，为新发现突变。结论Laron综合征患者存在典型的面貌特征，结合血GH、IGF-I、IGFBP-3和GHBP测定可以明确诊断。GHR基因外显子4上S65H突变可能是该Laron综合征患者的致病原因。     

Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation

STAT5 proteins are components of the common growth hormone and interleukin 2 family of cytokines' signaling pathway. Mutations in the STAT5b gene, described in 2 patients, lead to growth hormone insensitivity that resembles Laron syndrome. Clinical immunodeficiency was also present, although immunologic defects have not been well characterized thus far. Here we describe a 16-year-old girl who suffered generalized eczema and recurrent infections of the skin and respiratory tract since birth. She also suffered severe chronic lung disease and multiple episodes of herpetic keratitis. Clinical features of congenital growth hormone deficiency were observed, such as persistently low growth rate, severely delayed bone age, and postnatal growth failure resulting from growth hormone resistance. This combined phenotype of growth hormone insensitivity and immunodeficiency was attributable to a homozygous C-->T transition that resulted in a nonsense mutation at codon 152 in exon 5 of the STAT5b gene. This novel mutation determined a complete absence of protein expression. The main immunologic findings were moderate T-cell lymphopenia (1274/mm3), normal CD4/CD8 ratio, and very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells. T cells presented a chronically hyperactivated phenotype. In vitro T-cell proliferation and interleukin 2 signaling were impaired. CD4+ and CD25+ regulatory T cells were significantly diminished, and they probably contributed to the signs of homeostatic mechanism deregulation found in this patient. This new case, in accordance with 2 previously reported cases, definitely demonstrates the significant role of the STAT5b protein in mediating growth hormone actions. Furthermore, the main immunologic findings bring about an explanation for the clinical immunodeficiency features and reveal for the first time the relevant role of STAT5b as a key protein for T-cell functions in humans.     

Effects of insulin-like growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insentivity syndrome

Underwood LE, Backelijau P, Duncan V, and the GHIS Collaborative Group. Effects of insulinlike growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insensitivity syndrome. Acta Paediatr 1999; Suppl 428:182-4. Stockholm. ISSN 0803-5326
Eight children with growth hormone insensitivity syndrome (GHIS) have been treated with injections of recombinant human insulin-like growth factor I (rh1GF-I) for more than 5 years each. After good acceleration of growth in the first year of therapy, the growth rade decreased to an average of 5-6 cm/year. In general, growth with IGF-I therapy is less exuberant than that observed with growth hormone (GH) therapy in GH-deficient children. IGF is well tolerated, though there may be overgrowth of the lymphoid tissues and the kidneys. Bone mineral density is improved by treatment. The benefits of therapy appear to exceed the risks. □ Growth hormone insensitivity syndrome, insulin-like growth factor I therapy, Laron syndrome