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- Title
Growth Hormone Receptor (GHR) 6O Pseudoexon Activation: A Novel Cause of Severe Growth Hormone Insensitivity.
- Authors
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; Storr, Helen L.
- 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.
- Subjects
CAMPANIA (Italy); ITALY; SOMATOTROPIN receptors; SOMATOTROPIN; HETEROZYGOSITY; RNA splicing; TRANSMEMBRANE domains; SHORT stature
- Publication
Journal of Clinical Endocrinology & Metabolism, 2022, Vol 107, Issue 1, pe401
- ISSN
0021-972X
- Publication type
Article
- DOI
10.1210/clinem/dgab550