PURPOSE To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. METHODS We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. RESULTS Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060). CONCLUSION MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

中文翻译：

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影响 MEPE 不同领域的变异与两种不同的骨疾病相关，即颅面骨缺损和耳硬化症。

目的 描述与遗传性先天性面瘫 (HCFP) 家族和耳硬化症有关的新分子因素。方法 我们在一个四代家族中进行了外显子组测序，该家族呈现非进行性 HCFP 和混合性听力损失 (HL)。MEPE 使用 Sanger 测序或分子倒置探针结合大规模平行测序对 89 个耳硬化症家族、1604 名无关受影响的受试者和 1538 名未筛选的对照进行分析。结果 HCFP 家族中的外显子组测序导致在 MEPE 中鉴定出一种罕见的分离杂合移码变体 p.(Gln425Lysfs*38)。由于该家族的 HL 表型类似于耳硬化症，我们在一个大型耳硬化症队列中进行了变异负荷和方差成分分析，并证明无意义和移码 MEPE 变异在受影响的受试者中显着富集（p = 0.0006-0.0060）。结论 MEPE 通过两个结构域发挥其在骨稳态中的作用，一个 RGD 和一个酸性富含丝氨酸天冬氨酸的 MEPE 相关 (ASARM) 基序，分别抑制骨吸收和矿化。预计与耳硬化症相关的所有变体都会导致无意义介导的衰变或 ASARM 和 RGD 截断的 MEPE。预计 HCFP 变体会产生具有完整 RGD 基序的 ASARM 截短的 MEPE。这种对蛋白质影响的差异与两种疾病的假定病理生理学相对应，并为不同的表型结果提供了合理的分子解释。