Growth Hormone Receptor (GHR) 6 Omega Pseudoexon Activation: A Novel Cause of Severe Growth Hormone Insensitivity

Cottrell, Emily; Maharaj, Avinaash; Williams, Jack; Chatterjee, Sumana; Cirillo, Grazia; del Giudice, Emanuele Miraglia; Festa, Adalgisa; Palumbo, Stefania; Capalbo, Donatella; Salerno, Mariacarolina; Pignata, Claudio; Savage, Martin O.; Schilbach, Katharina; Bidlingmaier, Martin; Hwa, Vivian; Metherell, Louise A.; Grandone, Anna und Storr, Helen L. (2022): Growth Hormone Receptor (GHR) 6 Omega Pseudoexon Activation: A Novel Cause of Severe Growth Hormone Insensitivity. In: Journal of Clinical Endocrinology & Metabolism, Bd. 107, Nr. 1, E401-E416

Abstract

Context: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies. Objective: This work aims to identify the genetic cause of growth failure in 3 classical GHI individuals. Methods: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6 Omega pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. Results: We identified a novel homozygous intronic GHR variant (g.5:42700940 T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6 Psi GHR pseudoexon mutation in the index patient.Two siblings also harbored the novel intronic 6 Omega pseudoexon GHR variant in compound heterozygosity with the known GHRc.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6 Omega pseudoexon not identified in wild-type constructs. Inclusion of the 6 Omega pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains.The truncated 6 Omega pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation. Conclusion: Novel GHR 6 Omega pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure.The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-972X
• Sprache: Englisch