|Year : 2019 | Volume
| Issue : 2 | Page : 83-88
A novel homozygous point mutation and deletion in exon 3 of growth hormone receptor causes laron syndrome: A case study
Department of Pediatrics, College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
|Date of Submission||15-Mar-2019|
|Date of Acceptance||24-Mar-2019|
|Date of Web Publication||30-Jul-2019|
Dr. Mosleh Jabari
Department of Pediatrics, College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh
Source of Support: None, Conflict of Interest: None
Laron syndrome is mainly an autosomal recessive disorder that is caused by the body's inability to utilize the growth hormone (GH) secreted by the pituitary gland. As the name suggests, GH is an important hormone that regulates the overall growth of the body throughout the lifetime of an individual. GH exerts its effect on binding to the GH receptors (GHRs), which thereby initiate a signaling cascade resulting in the production of insulin-like growth factors (IGFs). Clinically, individuals with Laron syndrome harbor mutations in the gene encoding GHR, which results in normal to high serum GH levels, negligible or no IGF1 production, low levels of GH binding proteins, hypoglycemia, and high insulin sensitivity. Physically, these individuals have short physical stature (dwarfism), obesity, hypogonadism (in males), protruding forehead and saddle nose, blue sclera, and high-pitched voice (in females). GHR mutations that cause the various anomalies associated with Laron syndrome generally occur within introns, exons, or splice sites. Here, we report for the first time, a combination of a homozygous point mutation (Cys119Phe) and a deletion within exon 3 in a 3-year-old boy from Saudi Arabia who was evaluated as having Laron syndrome. The boy is currently being treated with IGF1 therapy.
Keywords: Dwarfism, exon, growth hormone receptor, insulin-like growth factor 1, Laron syndrome, mutations
|How to cite this article:|
Jabari M. A novel homozygous point mutation and deletion in exon 3 of growth hormone receptor causes laron syndrome: A case study. Imam J Appl Sci 2019;4:83-8
|How to cite this URL:|
Jabari M. A novel homozygous point mutation and deletion in exon 3 of growth hormone receptor causes laron syndrome: A case study. Imam J Appl Sci [serial online] 2019 [cited 2020 Jan 22];4:83-8. Available from: http://www.e-ijas.org/text.asp?2019/4/2/83/263664
| Introduction|| |
Laron syndrome is an autosomal recessive disorder that is caused by the inability to utilize the growth hormone (GH) which is an important hormone that regulates theoverall growth of the body throughout the life-time of an individual. GH exerts its effect upon binding to the GH receptors(GHR), which thereby initiate a signaling cascade resulting in the production of insulin-like growth factors (IGF). Clinically, individuals with Laron syndrome harbor mutations in the gene encoding GHR, which results in normal to high serum GH levels, negligible or no IGF1 production, low levels of GH binding proteins (GHBP), hypoglycemia, and high insulin sensitivity. Physically, these individuals have short physical stature, obesity, hypogonadism (in males), protruding forehead and saddle nose, blue sclera, and high-pitched voice (in females).
| Case Report|| |
A 3-year-old Saudi Arabian boy presented with a fracture in the right femur in November 2016. The fracture was remedied surgically, and the boy recovered and resumed normal activities. However, he was found to be three standard deviations (SDs) below the average height and weight of a boy of his age (height – 72 cm and weight – 8 kg), although his height and weight were normal at birth. The heights of his parents, who are first-degree relatives, are normal (father – 163 cm and mother – 158 cm). The boy has frontal bossing, depressed nose-bridge, and blue sclera, which are indicative of growth hormone (GH) insensitivity or Laron syndrome. Pathological analysis revealed normal calcium, phosphate, creatinine, free T4 and thyroid-stimulating hormone, and human tissue antibody levels and complete blood count. However, he had unusually high basal GH levels (>800 ng/mL; reference range is ≤6.7 ng/mL) and low serum insulin-like growth factor 1 (IGF1; <10 ng/mL, reference range is 13–143 ng/mL) and IGF-binding protein 3 (IGF-BP3; 360 ng/mL, reference range is 1410–2980 ng/mL) levels. These results suggested the presence of either Laron syndrome (resistance to GH due to mutations in GH receptor [GHR)] or biologically an inactive GH. IGF1 generation test confirmed Laron syndrome. Further, the boy's blood sample was sent for sequencing and deletion/duplication analysis to Centogene AG for molecular analysis of the cause underlying the syndrome. The GHR sequencing results (NM_001242399.2) showed that the boy harbored a novel homozygous single point mutation (c. 356 G < T), which resulted in a Cys119Phe substitution in a highly conserved region of the protein. Software analysis indicated this mutation to be potentially damaging and likely pathogenic (Class 2 variant according to the American College of Medical Genetics and Genomics (ACMG) recommendations and Centogene variant classification). In addition, this homozygous mutation is not yet described in the Exome Aggregation Consortium, the Exome Sequencing Project or the 1000 Genomes browser, and neither was it present in CentoMD 3.2 database. However, a pathogenic amino acid change at this position (Cys119Ser) has been described by Fang et al. as the primary cause of GH insensitivity (GHIS) and IGF1 deficiency in an Austrian family. No other pathogenic variants were detected by sequencing.
However, since sequencing of exon 3 was not possible, multiplex ligation-dependent probe amplification (MLPA) analysis was used, which detected a homozygous deletion encompassing exon 3 of GHR. GHR alleles harboring similar deletions in exon 3 GHR occur naturally in humans as a consequence of homologous recombination between retroviral repeats within this exon. However, this deletion has been classified as benign (Class 5) per ACMG recommendations.
The patient would be started on subcutaneous recombinant IGF1 therapy (120 μg/kg) daily, and growth velocity would be monitored during the treatment.
| Method of Genetic Testing|| |
Both DNA strands of the entire coding region of GHR were sequenced. The entire gene was analyzed by both sequencing and PCR, including the highly conserved intron–exon splice junctions. MLPA analysis was performed using the SALSA MLPA probe mix P262-A2 (MRC, Holland) to identify duplications and deletions within the entire gene. Software analysis was performed using Polyphen, SIFT, and Align-GVGD to predict the damaging potential of the mutants.
| Discussion|| |
In this study, we report the case of a 3-year-old boy who was evaluated as having Laron syndrome based on physical characteristics and biochemical parameters. Individuals with Laron syndrome have short stature (dwarfism), depressed nasal bridge, mandibular underdevelopment, prominent forehead, and truncal obesity. For example, the heights of the Ecuadorian individuals with GHIS of the Loja cohort are 6.7–10.0 SD below the normal mean height for age in the United States. Of 20 patients, 15 had limited elbow extensibility, and all affected adults had blue sclerae and relatively short limbs. The basal serum concentrations of GH were elevated in all affected children and normal to moderately elevated in the adults. The levels of circulating GHBP were 1%–30% of the normal level. In addition, Ecuadorian individuals with Laron syndrome of the El Oro cohort had normal body proportions in childhood but childlike proportions in adults, disproportionately greater deviation of stature than head size, blue sclerae, and limited elbow extension. The proband identified in this study also showed certain physical features that are associated with Laron syndrome described above, such as short stature (three SDs below the average), blue sclerae, depressed nasal bridge, frontal bossing, low serum levels of IGF-BP3 and IGF1, and abnormally high levels of GH.
Laron syndrome or GHIS, an autosomal recessive disorder that is characterized by insensitivity to GH, was first identified in 1958 by Zvi Laron, and occurred mostly in Semitic people of the Jewish extraction. A sizeable number of cases has also been reported in south Ecuadorian communities of the Loja and El Oro province, who are believed to be descendants of a Sephardic Jew who immigrated to Ecuador during the Spanish Inquisition., GH, produced by the pituitary gland, acts on GHR, a glycosylated membrane protein encoded by a single gene with ten exons on human chromosome 5. GHR occurs predominantly on the surface of hepatic cells, and mature GHR consists of 620 amino acids, which are organized into three structural domains, namely an extracellular domain encoded by exons 2–7, a transmembrane domain encoded by exon 8, and an intracellular domain encoded by exons 9–10. The extracellular domain consists of two functional subdomains; subdomain 1 (encoded by exons 2–5) is involved in GH-GHR interactions, whereas subdomain 2 is predominantly involved in receptor dimerization on GH-GHR interaction. A soluble proteolytic fragment of the extracellular domain of the full-length GHR circulates as GHBP, which is used as a diagnostic marker for the presence of functional GHR., Ligand–receptor binding subsequently leads to the production of somatomedins such as IGF1. IGF1 acts on IGF1 receptor expressed on various cell surfaces to affect growth and metabolism.
In 1993, Argetsinger et al. showed that JAK2 mediates signaling by the GHR. Frank et al. further demonstrated that JAK2 binds constitutively to the Box 1 sequence of GHR. The Waters laboratory characterized the first knockin mouse models to determine which specific regions of the GHR cytoplasmic domain are required for GH actions.,, These mice, with targeted mutations of GHR, expressed GHR proteins either truncated at proline m569, together with the conversion of tyrosines m539 and m545 to phenylalanine (mutant 569), or truncated at lysine m391 (mutant 391). A third mutant (GHR–/– mice) was created wherein the Box 1 motif of the GHR was disabled by four Pro/Ala mutations. These models showed that JAK2 and STAT5 signaling is essential for normal postnatal growth.,
The Kopchick laboratory has done extensive work on GHR-knockout (GHRKO) mice.,,,,,,,,,,, The patients in our study were GH resistant, had retarded growth, high GH levels, and low IGF1, similar to the GH-resistant mice in the Kopchick laboratory. GHRKO mice were also obese yet insulin sensitive, had increased adiposity, less muscle mass, were resistant to cancer and diet-induced diabetes, had an extended lifespan, retarded aging, and enhanced cognitive performance. Following are some recent reports from the Kopchick laboratory. Junnila et al. found delayed growth, increased adiposity, and improved insulin sensitivity in 6-week-old adult-onset GHRKO mice similar to the benefits found in GHRKO mice. Gesing et al. crossed Ames dwarf mice (df/df) (deficient in GH) and GHRKO to produce a new mouse line (df/KO), lacking both GH and GHR, which had improved glucose tolerance and extended longevity. Brooks et al. demonstrated that circulating fibroblast growth factor 21 (FGF21) levels were significantly increased in bovine GH transgenic mice, but remained unchanged in GHR–/– mice, suggesting possible modulation of FGF21 by GH. Sadagurski et al. concluded that early-life disruption of GH signaling produced long-term hypothalamic changes that may contribute to the longevity of GH-resistant mice. Cordoba-Chacon et al. observed an increase in hepatic de novo lipogenesis (DNL) in GHR knockdown (aLivGHRkd) mice and postulated that loss of the inhibitory hepatic GH increases hepatic DNL observed in nonalcoholic fatty liver disease patients. Stout et al. demonstrated a positive association between GH activity, age-related white adipose tissue (WAT) dysfunction, and WAT senescent cell accumulation in mice. Rojanathammanee et al. found that the detoxification and stress response mechanisms in GHRKO mice are contributed partly by the circulating level of IGF-1.
Various mutations in GHR disrupts the GH-IGF1 signaling pathway and the negative feedback effect of IGF1 on GH production, which results in normal to elevated GH levels and deficiencies in IGF1 and circulating GHBP levels observed in Laron syndrome. Majority of the characterized GHR mutations affect the extracellular domain of GHR.,,,,, However, several mutations in the exons encoding the intracellular domain have also been identified. For example, a homozygous G to C transversion at the -1 position in the splice donor site of exon 8 results in the complete elimination of exon 8 from the GHR mRNA, and the mutant GHR lacks the transmembrane and intracellular domains. Similarly, a heterozygous point mutation of the donor splice site in intron 9 of GHR in two Japanese siblings with GHIS resulted in complete skipping of exon 9 and the introduction of a premature stop codon in exon 10 in only one allele. Currently, more than 70 unique GHR mutations from more than 250 patients are known, which include missense, nonsense, and splice-site mutations, insertions, and deletions.,, In particular, splice-site mutations that either eliminate existing splice sites or introduce new sites can cause exon or multicodon deletion,,,,,,, or insertion in the GHR mRNA. Metherell et al. reported the activation of a mutant pseudoexon by an A(-1) to G(-1) at the 5' pseudoexon splice site, which results in the addition of extra 108 nucleotides between exons 6 and 7 in four children with GHIS.
Most of the GHR mutations are homozygous. However, Goddard et al. examined the genotype of 14 children with idiopathic short stature and GHIS and identified three mutations in GHR, which might be responsible for the low serum level of GHBP but normal GH. These mutations were (i) a compound heterozygosity for a G-to-A transition at position 184 in exon 4 of GHR, resulting in a Glu44 Lys substitution, and a C-to-T transition at position 535 in exon 6, resulting in an Arg161Cys amino acid substitution; (ii) an Arg161Cys mutation; and (iii) a mutation at nucleotide position 726 of GHR that introduced an aspartic acid in place of glutamic acid at position 224.
Ayling et al. identified a dominant-negative mutation of GHR in a mother and daughter with GHIS who did not exhibit the usual phenotype associated with this syndrome. The abnormality was not detected in the maternal grandparents, indicating a de novo mutation in the proband's mother. The mutation involved a G-to-C transversion at position -1 of the splice acceptor site of intron 8, which resulted in skipping of exon 9 during splicing and a concomitant frameshift mutation that generated a premature stop codon such that the intracellular domain of the truncated GHR contained only seven amino acids. This compromised the JAK-STAT signaling downstream of GHR and lowered IGF1 levels.
Fang et al. identified two heterozygous missense mutation in codons 94 (which is the same as codon 119 according to the changed nomenclature) and 105 of GHR. The compound heterozygote GHR and the single heterozygote GHR Cys94Ser were severely compromised in GH binding and were responsible for the GHI observed in the two daughters of an Austrian family. In this study, we detected a previously unreported homozygous G to T substitution in the same codon (Cys119 Phe), which is classified as a Type 2 variation in terms of its pathogenicity. In addition, we detected a deletion in exon 3, which has been associated with this syndrome. Similar naturally occurring deletions have been reported by Pantel et al., where the entire exon 3 is deleted by homologous recombination between retroviral repeat sequences flanking this exon. Palizban et al. reported the existence of homozygous GHR exon 3 deletions as a polymorphism in 19% of the Iranian population, whereas Wassenaar et al. detected this deletion in 12% of asymptomatic patients, which was hence classified to be a class 5 (benign) variant. This is the first time that this novel homozygous substitution mutation has been associated with symptomatic Laron syndrome and it adds to the growing list of mutations in the extracellular domain in GHR that contributes to the pathogenesis of the disease. However, whether the presence of the substitution mutation alone (not in combination with the exon 3 deletion) can elicit Laron syndrome-like symptoms is unclear, and future studies are required to understand whether this mutation alone compromises GH binding and subsequent downstream signaling.
In a recent report, Hinrichs et al. established a large animal model for Laron syndrome by generating pigs with GHRKO mutations using CRISPR/Cas9 technology to mutate exon 3 of the GHR gene in porcine zygotes. GHR-deficient pigs revealed postnatal growth retardation, disproportionate organ growth, increased total body fat content, elevated serum GH concentrations, markedly reduced serum IGF1 and IGFBP3 levels, transient juvenile hypoglycemia, increased expression and phosphorylation of insulin receptor substrate 1 in the liver suggesting increased insulin sensitivity, reduced phosphorylation of STAT5, and increased phosphorylation of JAK2. The authors concluded that GHRKO pigs resemble the pathophysiology of Laron syndrome and are an interesting model for mechanistic studies and treatment trials.
Currently, IGF1 therapy is used for treating Laron syndrome. The first evidence showing that IGF1 could reverse certain biochemical aspects associated with Laron syndrome in vitro was provided by Geffner et al. Later, several researchers have used IGF1 on various patients with this syndrome and reported beneficial effects. For example, Walker et al. found a reduction in fasting blood glucose level on IGF1 administration, which reflects its insulin-like properties. Laron et al. observed increased linear growth velocity, increase in head circumference and body weight, and a reduction in subcutaneous fat when IGF1 was administered subcutaneously once daily for 3–10 months in 5 children aged 3.3–14.5 years. Backeljauw et al. treated 8 children with GHIS syndrome, 5 with GHR deficiency (Laron syndrome) and 3 with growth-attenuating antibodies to GH, with recombinant IGF1 for 24 months and observed statural growth for at least 2 years; however, growth response was not as intense as that observed in GH-treated patients with GH deficiency, possibly because GH directly affects bone growth unlike IGF1. Laron et al. found that daily administration of IGF1 (120 micrograms/kg) for 9 months in five adult patients with Laron syndrome resulted in beneficial anthropometric and metabolic changes. However, there was a reversal of these changes on discontinuation of IGF1 treatment. Mauras et al. investigated the in vivo effects of 8 weeks of therapy with recombinant human IGF1 in a cohort of 10 adult Ecuadorian GHIS subjects and concluded that IGF1 may be beneficial as long-term replacement therapy for adult patients with Laron syndrome. Considering the overall effectiveness of IGF1 treatment over GH therapy in treating Laron syndrome, we have decided to treat the proband identified in this report with subcutaneous IGF1 therapy twice daily in the near future.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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| References|| |
Fang P, Riedl S, Amselem S, Pratt KL, Little BM, Haeusler G, et al.
Primary growth hormone (GH) insensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the GH receptor gene: Genetic and functional studies of simple and compound heterozygous states. J Clin Endocrinol Metab 2007;92:2223-31.
Pantel J, Machinis K, Sobrier ML, Duquesnoy P, Goossens M, Amselem S. Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution. J Biol Chem 2000;275:18664-9.
Rosenbloom AL, Guevara Aguirre J, Rosenfeld RG, Fielder PJ. The little women of Loja – Growth hormone-receptor deficiency in an inbred population of Southern Ecuador. N Engl J Med 1990;323:1367-74.
Guevara-Aguirre J, Rosenbloom AL, Vaccarello MA, Fielder PJ, de la Vega A, Diamond FB Jr., et al.
Growth hormone receptor deficiency (Laron syndrome): Clinical and genetic characteristics. Acta Paediatr Scand Suppl 1991;377:96-103.
Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentration of growth hormone – A new inborn error of metabolism? Isr J Med Sci 1966;2:152-5.
Behncken SN, Waters MJ. Molecular recognition events involved in the activation of the growth hormone receptor by growth hormone. J Mol Recognit 1999;12:355-62.
Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, et al.
Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol 2005;12:814-21.
Bondy CA, Underwood LE, Clemmons DR, Guler HP, Bach MA, Skarulis M, et al.
Clinical uses of insulin-like growth factor I. Ann Intern Med 1994;120:593-601.
Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, et al.
Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 1993;74:237-44.
Frank SJ, Gilliland G, Kraft AS, Arnold CS. Interaction of the growth hormone receptor cytoplasmic domain with the JAK2 tyrosine kinase. Endocrinology 1994;135:2228-39.
Rowland JE, Lichanska AM, Kerr LM, White M, d'Aniello EM, Maher SL, et al. In vivo
analysis of growth hormone receptor signaling domains and their associated transcripts. Mol Cell Biol 2005;25:66-77.
Waters MJ, Hoang HN, Fairlie DP, Pelekanos RA, Brown RJ. New insights into growth hormone action. J Mol Endocrinol 2006;36:1-7.
Barclay JL, Kerr LM, Arthur L, Rowland JE, Nelson CN, Ishikawa M, et al. In vivo
targeting of the growth hormone receptor (GHR) box1 sequence demonstrates that the GHR does not signal exclusively through JAK2. Mol Endocrinol 2010;24:204-17.
Waters MJ, Brooks AJ. JAK2 activation by growth hormone and other cytokines. Biochem J 2015;466:1-1.
Waters MJ. The growth hormone receptor. Growth Horm IGF Res 2016;28:6-10.
Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, et al.
A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A 1997;94:13215-20.
Bartke A, Chandrashekar V, Turyn D, Steger RW, Debeljuk L, Winters TA, et al.
Effects of growth hormone overexpression and growth hormone resistance on neuroendocrine and reproductive functions in transgenic and knock-out mice. Proc Soc Exp Biol Med 1999;222:113-23.
Kinney BA, Coschigano KT, Kopchick JJ, Steger RW, Bartke A. Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav 2001;72:653-60.
Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ, et al.
Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 2003;144:3799-810.
Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, et al.
Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 2012;11:73-81.
Giani JF, Miquet JG, Muñoz MC, Burghi V, Toblli JE, Masternak MM, et al.
Upregulation of the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in the heart and the kidney of growth hormone receptor knock-out mice. Growth Horm IGF Res 2012;22:224-33.
Kopchick JJ, List EO, Kelder B, Gosney ES, Berryman DE. Evaluation of growth hormone (GH) action in mice: Discovery of GH receptor antagonists and clinical indications. Mol Cell Endocrinol 2014;386:34-45.
Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol 2013;9:366-76.
Comisford R, Lubbers ER, Householder LA, Suer O, Tchkonia T, Kirkland JL, et al.
Growth hormone receptor antagonist transgenic mice have increased subcutaneous adipose tissue mass, altered glucose homeostasis and no change in white adipose tissue cellular senescence. Gerontology 2016;62:163-72.
Young JA, List EO, Kopchick JJ. Deconstructing the growth hormone receptor (GHR): Physical and metabolic phenotypes of tissue-specific GHR gene-disrupted mice. Prog Mol Biol Transl Sci 2016;138:27-39.
Duran-Ortiz S, Noboa V, Kopchick JJ. Disruption of the GH receptor gene in adult mice and in insulin sensitive tissues. Growth Horm IGF Res 2018;38:3-7.
Basu R, Qian Y, Kopchick JJ. Mechanisms in endocrinology: Lessons from growth hormone receptor gene-disrupted mice: Are there benefits of endocrine defects? Eur J Endocrinol 2018;178:R155-81.
Junnila RK, Duran-Ortiz S, Suer O, Sustarsic EG, Berryman DE, List EO, et al.
Disruption of the GH receptor gene in adult mice increases maximal lifespan in females. Endocrinology 2016;157:4502-13.
Gesing A, Wiesenborn D, Do A, Menon V, Schneider A, Victoria B, et al.
A long-lived mouse lacking both growth hormone and growth hormone receptor: A new animal model for aging studies. J Gerontol A Biol Sci Med Sci 2017;72:1054-61.
Brooks NE, Hjortebjerg R, Henry BE, List EO, Kopchick JJ, Berryman DE, et al.
Fibroblast growth factor 21, fibroblast growth factor receptor 1, and β-klotho expression in bovine growth hormone transgenic and growth hormone receptor knockout mice. Growth Horm IGF Res 2016;30-31:22-30.
Sadagurski M, Landeryou T, Cady G, Kopchick JJ, List EO, Berryman DE, et al.
Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice. Aging Cell 2015;14:1045-54.
Cordoba-Chacon J, Majumdar N, List EO, Diaz-Ruiz A, Frank SJ, Manzano A, et al.
Growth hormone inhibits hepatic de novo
lipogenesis in adult mice. Diabetes 2015;64:3093-103.
Stout MB, Tchkonia T, Pirtskhalava T, Palmer AK, List EO, Berryman DE, et al.
Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY) 2014;6:575-86.
Rojanathammanee L, Rakoczy S, Kopchick J, Brown-Borg HM. Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice. Age (Dordr) 2014;36:9687.
Amselem S, Duquesnoy P, Duriez B, Dastot F, Sobrier ML, Valleix S, et al.
Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet 1993;2:355-9.
Ayling RM, Ross R, Towner P, Von Laue S, Finidori J, Moutoussamy S, et al.
A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet 1997;16:13-4.
Berg MA, Guevara-Aguirre J, Rosenbloom AL, Rosenfeld RG, Francke U. Mutation creating a new splice site in the growth hormone receptor genes of 37 ecuadorean patients with Laron syndrome. Hum Mutat 1992;1:24-32.
Berg MA, Argente J, Chernausek S, Gracia R, Guevara-Aguirre J, Hopp M, et al.
Diverse growth hormone receptor gene mutations in Laron syndrome. Am J Hum Genet 1993;52:998-1005.
Otsuka T, Iwatani N, Kodama M, Sakakida M, Shichiri M, Jinno Y, et al.
The growth hormone receptor gene mutation of a Japanese patient with Laron syndrome. Jpn J Hum Genet 1997;42:323-9.
Silbergeld A, Dastot F, Klinger B, Kanety H, Eshet R, Amselem S, et al.
Intronic mutation in the growth hormone (GH) receptor gene from a girl with Laron syndrome and extremely high serum GH binding protein: Extended phenotypic study in a very large pedigree. J Pediatr Endocrinol Metab 1997;10:265-74.
Woods KA, Fraser NC, Postel-Vinay MC, Savage MO, Clark AJ. A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. J Clin Endocrinol Metab 1996;81:1686-90.
Iida K, Takahashi Y, Kaji H, Nose O, Okimura Y, Abe H, et al.
Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab 1998;83:531-7.
Laron Z. Laron syndrome (primary growth hormone resistance or insensitivity): The personal experience 1958-2003. J Clin Endocrinol Metab 2004;89:1031-44.
Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 1994;15:369-90.
Savage MO, Attie KM, David A, Metherell LA, Clark AJ, Camacho-Hübner C. Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders. Nat Clin Pract Endocrinol Metab 2006;2:395-407.
Metherell LA, Akker SA, Munroe PB, Rose SJ, Caulfield M, Savage MO, et al.
Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. Am J Hum Genet 2001;69:641-6.
Goddard AD, Covello R, Luoh SM, Clackson T, Attie KM, Gesundheit N, et al.
Mutations of the growth hormone receptor in children with idiopathic short stature. The growth hormone insensitivity study group. N Engl J Med 1995;333:1093-8.
Palizban AA, Radmansorry M, Bozorgzad M. Exon 3-deleted and full-length growth hormone receptor polymorphism frequencies in an Iranian population. Res Pharm Sci 2014;9:489-94.
Wassenaar MJ, Dekkers OM, Pereira AM, Wit JM, Smit JW, Biermasz NR, et al.
Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: A systematic review and meta-analysis. J Clin Endocrinol Metab 2009;94:3721-30.
Hinrichs A, Kessler B, Kurome M, Blutke A, Kemter E, Bernau M, et al.
Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver. Mol Metab 2018;11:113-28.
Geffner ME, Golde DW, Lippe BM, Kaplan SA, Bersch N, Li CH. Tissues of the laron dwarf are sensitive to insulin-like growth factor I but not to growth hormone. J Clin Endocrinol Metab 1987;64:1042-6.
Walker JL, Ginalska-Malinowska M, Romer TE, Pucilowska JB, Underwood LE. Effects of the infusion of insulin-like growth factor I in a child with growth hormone insensitivity syndrome (Laron dwarfism). N Engl J Med 1991;324:1483-8.
Laron Z, Anin S, Klipper-Aurbach Y, Klinger B. Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism. Lancet 1992;339:1258-61.
Backeljauw PF, Underwood LE. Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome – A clinical research center study. GHIS collaborative group. J Clin Endocrinol Metab 1996;81:3312-7.
Guevara-Aguirre J, Rosenbloom AL, Vasconez O, Martinez V, Gargosky SE, Allen L, et al.
Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: Comparison of two dosage levels and to GH-treated GH deficiency. J Clin Endocrinol Metab 1997;82:629-33.
Laron Z, Klinger B. IGF-I treatment of adult patients with Laron syndrome: Preliminary results. Clin Endocrinol (Oxf) 1994;41:631-8.
Mauras N, Martinez V, Rini A, Guevara-Aguirre J. Recombinant human insulin-like growth factor I has significant anabolic effects in adults with growth hormone receptor deficiency: Studies on protein, glucose, and lipid metabolism. J Clin Endocrinol Metab 2000;85:3036-42.