Clinical dysmorphology · 2025
Recurrent platelet-derived growth factor receptor beta gene mutations in Kosaki overgrowth syndrome: a molecular and clinical overview.
СтатьяОбзорНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Gladkauskas Titas, Cristea Ileana, Mehrasa Roya, Bruland Ove, Rustad Cecilie F, Faivre Laurence, Rødahl Eyvind, Bredrup Cecilie
Аннотация
OBJECTIVE: Kosaki overgrowth syndrome (KOGS) is a rare genetic disorder linked to germline variants in the platelet-derived growth factor receptor beta gene ( PDGFRB ) that is characterized by postnatal overgrowth, hyperelastic skin, lipodystrophy, and craniofacial anomalies. This study aimed to summarize clinical and genetic data from reported KOGS cases and investigate the molecular consequences of two recurrent KOGS-associated PDGFRB variants.
METHODS: Clinical and genetic information from 17 previously published KOGS cases was reviewed. Molecular studies were performed using patient-derived fibroblasts and genetically modified cells transduced with the recurrent PDGFRB variants Trp566Arg and Pro584Arg. Downstream signaling and phosphorylation of PDGFRβ tyrosine residues were assessed by immunoblotting and immunocytochemistry.
RESULTS: Both variants induced phosphorylation of specific PDGFRβ tyrosine residues and activated downstream signaling pathways in the absence of ligand stimulation, which could contribute to the phenotypic overgrowth observed in KOGS. Immunocytochemistry revealed vesicle-like structures of phosphorylated PDGFRβ (pY740), resembling wild-type cells stimulated with growth factor, thereby supporting the constitutive activation of PDGFRβ in patient fibroblasts. Both variants showed sensitivity to the tyrosine kinase inhibitor imatinib.
CONCLUSION: Recurrent PDGFRB variants in KOGS cause ligand-independent activation of PDGFRβ, contributing to the overgrowth phenotype. Imatinib may represent a potential targeted therapeutic option.
METHODS: Clinical and genetic information from 17 previously published KOGS cases was reviewed. Molecular studies were performed using patient-derived fibroblasts and genetically modified cells transduced with the recurrent PDGFRB variants Trp566Arg and Pro584Arg. Downstream signaling and phosphorylation of PDGFRβ tyrosine residues were assessed by immunoblotting and immunocytochemistry.
RESULTS: Both variants induced phosphorylation of specific PDGFRβ tyrosine residues and activated downstream signaling pathways in the absence of ligand stimulation, which could contribute to the phenotypic overgrowth observed in KOGS. Immunocytochemistry revealed vesicle-like structures of phosphorylated PDGFRβ (pY740), resembling wild-type cells stimulated with growth factor, thereby supporting the constitutive activation of PDGFRβ in patient fibroblasts. Both variants showed sensitivity to the tyrosine kinase inhibitor imatinib.
CONCLUSION: Recurrent PDGFRB variants in KOGS cause ligand-independent activation of PDGFRβ, contributing to the overgrowth phenotype. Imatinib may represent a potential targeted therapeutic option.