{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:10:32Z","timestamp":1793157032501,"version":"4.5.0"},"reference-count":45,"publisher":"The Endocrine Society","issue":"1","license":[{"start":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T00:00:00Z","timestamp":1627430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Barts Charity Large Project","award":["MRC0161"],"award-info":[{"award-number":["MRC0161"]}]},{"name":"European Society for Paediatric Endocrinology Research Fellowship","award":["1010180"],"award-info":[{"award-number":["1010180"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This work aims to identify the genetic cause of growth failure in 3 \u201cclassical\u201d GHI individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6\u03a9 pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a novel homozygous intronic GHR variant (g.5:42700940T\u2005&amp;gt;\u2005G, c.618+836T\u2005&amp;gt;\u2005G), 44 bp downstream of the previously recognized intronic 6\u03a8 GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6\u03a9 pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C\u2005&amp;gt;\u2005T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6\u03a9 pseudoexon not identified in wild-type constructs. Inclusion of the 6\u03a9 pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6\u03a9 pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Novel GHR 6\u03a9 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgab550","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T07:39:52Z","timestamp":1627457992000},"page":"e401-e416","source":"Crossref","is-referenced-by-count":6,"title":["Growth Hormone Receptor\n                    <i>(GHR)<\/i>\n                    6\u03a9 Pseudoexon Activation: A Novel Cause of Severe Growth Hormone Insensitivity"],"prefix":"10.1210","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6773-6547","authenticated-orcid":false,"given":"Emily","family":"Cottrell","sequence":"first","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute, London EC1M 6BQ, 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