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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 4  |  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 Submission15-Mar-2019
Date of Acceptance24-Mar-2019
Date of Web Publication30-Jul-2019

Correspondence Address:
Dr. Mosleh Jabari
Department of Pediatrics, College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijas.ijas_5_19

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  Abstract 


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 2019 Oct 18];4:83-8. Available from: http://www.e-ijas.org/text.asp?2019/4/2/83/263664




  Introduction Top


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 Top


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.[1] as the primary cause of GH insensitivity (GHIS) and IGF1 deficiency in an Austrian family.[1] 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.[2] 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 Top


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 Top


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.[3] 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.[4] 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,[5] 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.[3],[4] 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.[6],[7] 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.[8]

In 1993, Argetsinger et al.[9] showed that JAK2 mediates signaling by the GHR. Frank et al.[10] 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.[11],[12],[13] 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.[14],[15]

The Kopchick laboratory has done extensive work on GHR-knockout (GHRKO) mice.[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27] 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.[28] 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.[29] 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.[30] 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.[31] 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.[32] 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.[33] demonstrated a positive association between GH activity, age-related white adipose tissue (WAT) dysfunction, and WAT senescent cell accumulation in mice. Rojanathammanee et al.[34] 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.[35],[36],[37],[38],[39],[40] 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.[41] 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.[42] 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.[43],[44],[45] In particular, splice-site mutations that either eliminate existing splice sites or introduce new sites can cause exon or multicodon deletion[35],[36],[37],[38],[39],[40],[41],[42] or insertion[46] in the GHR mRNA. Metherell et al.[46] 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.[46]

Most of the GHR mutations are homozygous. However, Goddard et al.[47] 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.[47]

Ayling et al.[36] 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.[1] 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.,[2] where the entire exon 3 is deleted by homologous recombination between retroviral repeat sequences flanking this exon. Palizban et al.[48] reported the existence of homozygous GHR exon 3 deletions as a polymorphism in 19% of the Iranian population, whereas Wassenaar et al.[49] 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.[50] 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.[51] Later, several researchers have used IGF1 on various patients with this syndrome and reported beneficial effects. For example, Walker et al.[52] found a reduction in fasting blood glucose level on IGF1 administration, which reflects its insulin-like properties. Laron et al.[53] 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.[54] 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.[55] Laron et al.[56] 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.[57] 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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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