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Absence of GP130 cytokine receptor signaling causes extended Stuve-Wiedemann syndrome.

ABSTRACT: The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

SUBMITTER: Chen YH

PROVIDER: S-EPMC7062520 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.

Chen Yin-Huai YH Grigelioniene Giedre G Newton Phillip T PT Gullander Jacob J Elfving Maria M Hammarsjö Anna A Batkovskyte Dominyka D Alsaif Hessa S HS Kurdi Wesam I Y WIY Abdulwahab Firdous F Shanmugasundaram Veerabahu V Devey Luke L Bacrot Séverine S Brodszki Jana J Huber Celine C Hamel Ben B Gisselsson David D Papadogiannakis Nikos N Jedrycha Katarina K Gürtl-Lackner Barbara B Chagin Andrei S AS Nishimura Gen G Aschenbrenner Dominik D Alkuraya Fowzan S FS Laurence Arian A Cormier-Daire Valérie V Uhlig Holm H HH

The Journal of experimental medicine 20200301 3

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal ...[more]

PMID: 31914175

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Project description:IntroductionPersistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition characterized by hypoxemia due to elevated pulmonary vascular resistance. PPHN commonly arises secondary to various underlying conditions, including infection, meconium aspiration, and respiratory distress syndrome. Management includes pulmonary vasodilators, mechanical ventilation, oxygen supplementation, vasopressors, and volume replacement. Stüve-Wiedemann syndrome (SWS), a rare genetic disorder characterized by bone dysplasia, respiratory distress, hyperthermia, and swallowing difficulties, may present with pulmonary hypertension, indicating a poor prognosis.Case descriptionA term female neonate presented with secondary respiratory failure and severe PPHN of unknown etiology on the second day of life, necessitating intubation. Clinical findings included facial dysmorphia, camptodactyly, skeletal anomalies, and generalized muscular hypotonia. High-frequency oscillation ventilation and surfactant administration yielded marginal improvement. On the third day of life, a severe pulmonary hypertensive crisis necessitated inhaled and systemic pulmonary vasodilators along with volume and catecholamine therapy. Whole exome sequencing revealed a homozygous mutation in the leukemia inhibitory factor receptor (LIFR) gene, consistent with Stüve-Wiedemann syndrome.Discussion/conclusionThe case underscores the importance of considering and prompting evaluation of rare genetic causes in the differential diagnosis of PPHN, especially when other abnormalities are present and conventional therapies prove inadequate. Therapeutic strategies must account for the different pathophysiology of primary PPHN including vascular remodeling, as seen in SWS, which may not respond to pulmonary vasodilators typically employed in secondary PPHN due to vasoconstriction. In this case, the patient responded well to treatment for primary PPHN, but the use of high-frequency oscillation ventilation and surfactant was not helpful.

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Absence of GP130 cytokine receptor signaling causes extended Stuve-Wiedemann syndrome.

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Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.

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