The Journal of experimental medicine · 2023
Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Bayard Charles, Segna Eleonora, Taverne Maxime, Fraissenon Antoine, Hennocq Quentin, Periou Baptiste, Zerbib Lola, Ladraa Sophia, Chapelle Célia, Hoguin Clément, Kaltenbach Sophie, Villarese Patrick, Asnafi Vahid, Broissand Christine, Nemazanyy Ivan, Autret Gwennhael, Goudin Nicolas, Legendre Christophe, Authier François-Jérôme, Viel Thomas, Tavitian Bertrand, Gitiaux Cyril, Fraitag Sylvie, Duong Jean-Paul, Delcros Clarisse, Sergent Bernard, Picard Arnaud, Dussiot Michael, Guibaud Laurent, Khonsari Roman, Canaud Guillaume
Аннотация
Hemifacial myohyperplasia (HFMH) is a rare cause of facial asymmetry exclusively involving facial muscles. The underlying cause and the mechanism of disease progression are unknown. Here, we identified a somatic gain-of-function mutation of PIK3CA in five pediatric patients with HFMH. To understand the physiopathology of muscle hypertrophy in this context, we created a mouse model carrying specifically a PIK3CA mutation in skeletal muscles. PIK3CA gain-of-function mutation led to striated muscle cell hypertrophy, mitochondria dysfunction, and hypoglycemia with low circulating insulin levels. Alpelisib treatment, an approved PIK3CA inhibitor, was able to prevent and reduce muscle hypertrophy in the mouse model with correction of endocrine anomalies. Based on these findings, we treated the five HFMH patients. All patients demonstrated clinical, esthetical, and radiological improvement with proof of target engagement. In conclusion, we show that HFMH is due to somatic alteration of PIK3CA and is accessible to pharmacological intervention.