1. Growth Hormone Receptor (GHR) 6O Pseudoexon Activation: A Novel Cause of Severe Growth Hormone Insensitivity.
- Author
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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, Metherel, Louise A., Grandone, Anna, and Storr, Helen L.
- Subjects
SOMATOTROPIN receptors ,SOMATOTROPIN ,HETEROZYGOSITY ,RNA splicing ,TRANSMEMBRANE domains ,SHORT stature - 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 6O 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.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6 GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6O pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6O pseudoexon not identified in wild-type constructs. Inclusion of the 6O pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6O pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation. Conclusion: Novel GHR 6O 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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