Lindsay Mark E, Scimone Eleanor R, Lawton Joseph, Richa Rashmi, Yonker Lael M, Di Yuanpu P, Buch Karen, Ouyang Wukun, Mo Xiulei, Lin Angela E, Mou Hongmei
Cardiovascular Genetics Program, Massachusetts General Hospital, Boston, Mass; Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Boston, Mass.
Medical Genetics, Department of Pediatrics, Mass General for Children, Boston, Mass.
J Allergy Clin Immunol. 2025 Jan;155(1):107-119.e2. doi: 10.1016/j.jaci.2024.08.024. Epub 2024 Sep 5.
Myhre syndrome is an exceedingly rare yet increasingly diagnosed genetic disorder arising from germline variants in the SMAD4 gene. Its core manifestation is the progression of stiffness and fibrosis across multiple organs. Individuals with Myhre syndrome exhibit a propensity for upper respiratory tract remodeling and infections. The molecular and cellular mechanisms underlying this phenotype remain unclear.
We sought to investigate how SMAD4 pathogenic variants associated with Myhre syndrome affect SMAD4 protein levels, activation, and physiological functions in patient-derived nasal epithelial cells.
Clinical observations were conducted on a cohort of 47 patients recruited at Massachusetts General Hospital from 2016 to 2023. Nasal epithelial basal cells were isolated and cultured from inferior turbinate brushings of healthy subjects (n = 8) and patients with Myhre syndrome (n = 3; SMAD4-Ile500Val, Arg496Cys, and Ile500Thr). Transcriptomic analysis and functional assays were performed to assess SMAD4 levels, transcriptional activity, and epithelial cell host defense functions, including cell proliferation, mucociliary differentiation, and bacterial elimination.
Clinical observations revealed a prevalent history of otitis media and sinusitis among most individuals with Myhre syndrome. Analyses of nasal epithelial cells indicated that SMAD4 mutations do not alter SMAD4 protein stability or upstream regulatory SMAD phosphorylation but enhance signaling transcriptional activity, supporting a gain-of-function mechanism, likely attributable to increased protein-protein interaction of the SMAD complex. Consequently, Myhre syndrome nasal basal cells exhibit reduced potential in cell proliferation and mucociliary differentiation. Furthermore, Myhre syndrome nasal epithelia are impaired in bacterial killing.
Compromised innate immunity originating from epithelial cells in Myhre syndrome may contribute to increased susceptibility to upper respiratory tract infections.
Myhre综合征是一种极为罕见但诊断率日益上升的遗传性疾病，由SMAD4基因的种系变异引起。其核心表现是多个器官的僵硬和纤维化进展。患有Myhre综合征的个体易出现上呼吸道重塑和感染。这种表型背后的分子和细胞机制仍不清楚。
我们试图研究与Myhre综合征相关的SMAD4致病变体如何影响患者来源的鼻上皮细胞中SMAD4蛋白水平、激活和生理功能。
对2016年至2023年在马萨诸塞州总医院招募的47名患者进行临床观察。从健康受试者（n = 8）和Myhre综合征患者（n = 3；SMAD4 - Ile500Val、Arg496Cys和Ile500Thr）的下鼻甲刷取物中分离并培养鼻上皮基底细胞。进行转录组分析和功能测定，以评估SMAD4水平、转录活性和上皮细胞宿主防御功能，包括细胞增殖、黏液纤毛分化和细菌清除。
临床观察发现，大多数Myhre综合征患者有中耳炎和鼻窦炎病史。鼻上皮细胞分析表明，SMAD4突变不会改变SMAD4蛋白稳定性或上游调节SMAD磷酸化，但会增强信号转录活性，支持功能获得机制，这可能归因于SMAD复合物的蛋白质 - 蛋白质相互作用增加。因此，Myhre综合征鼻基底细胞在细胞增殖和黏液纤毛分化方面的潜力降低。此外，Myhre综合征鼻上皮在细菌杀灭方面受损。
Myhre综合征中源自上皮细胞的先天免疫受损可能导致对上呼吸道感染的易感性增加。
