Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

Abstract

Background: To date, about sixty different mutations within GH receptor (GHR) gene have been described in patients with GH insensitivity syndrome (GHI). In this report, we described a novel nonsense mutation of GHR. Methods: The patient was evaluated at the age of 6 yr, for short stature associated to clinical phenotype of GHI. GH, IGF-1, and GHBP levels were determined. The PCR products from exons 2-10 were sequenced. Results: The patient had high GH (26 µg/L), low IGF-1 (22.5 ng/ml) and undetectable GHBP levels. The sequencing of GHR exon 5 disclosed adenine duplication at nucleotide 338 of GHR coding sequence (c.338dupA) in homozygous state. Conclusion: We described a novel mutation that causes a truncated GHR and a loss of receptor function due to the lack of amino acids comprising the transmembrane and intracellular regions of GHR protein, leading to GHI.

A Novel Y332C Missense Mutation in the Intracellular Domain of The Human Growth Hormone Receptor Does Not Alter STAT5b Signaling: Redundancy of GHR Intracellular Tyrosines Involved in STAT5b Signaling

“…To significantly perturb the IGF-I production so necessary for normal growth, mutations in the intracellular domain of GHR would need to disrupt the availability of all 3 critical tyrosines, Y534, Y566 and Y627, hence preventing, or at least significantly reducing, STAT5b signaling. Indeed, the handful of mutations identified in the intracellular domain of GHR that are clearly implicated in IGFD and GHI, involve significant DNA aberrations – frameshifts due to deletions, duplications [27] or splicing mutations [1,2] – which result in either premature protein truncations that abrogate all the critical tyrosines or destabilize the entire GHR protein structure. The prediction, therefore, would be that a simple homozygous missense mutation, even if within one of the critical tyrosines, would have minimal impact on STAT5b signaling, unless the mutation significantly compromised the structure of the GHR.…”

“…The critical importance of the growth hormone receptor (GHR) for human postnatal growth is validated by the identification of over 70 GHR mutations reported in more than 250 clinical cases of growth hormone insensitivity (GHI), characterized by normal-to-elevated GH and low insulin-like growth factor (IGF)-I [1,2]. GHR, a member of the type I class of the cytokine receptor superfamily, binds circulating GH, initiating signaling processes involving the STAT (signal transducer and activator of transcription), MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide-3 kinase) pathways.…”

“…In humans, the extracellular domain can be proteolytically cleaved to circulate in blood as GH-binding protein (GHBP). The majority of identified GHR mutations are located in sequences encoding the extracellular domain of GHR [1,2]. Indeed, most of the characterized GHI patients have abnormally low levels of serum GHBP, thus making GHBP a useful marker of GHR expression.…”

“…These cases suggest defects that either involve the transmembrane or intracellular domains of the GHR, or are downstream of the GHR. To date, the few described mutations in the intracellular portion of GHR have involved small deletions that result in frameshifts and subsequent premature protein termination [1,2]. Downstream of GHR, 5 mutations in the STAT5b gene have been recently identified [5].…”

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

“…It is classically associated with mutations in the GH receptor (GHR; OMIM: *600946), and is transmitted in an autosomal recessive manner (1,2).…”