Peripherin 2 (PRPH2) is a retina-specific tetraspanin protein essential for the formation of rod and cone photoreceptor outer segments (OS). Patients with mutations in PRPH2 exhibit severe retinal degeneration characterized by vast inter- and intra-familial phenotypic heterogeneity. To help understand contributors to this within-mutation disease variability, we asked whether the PRPH2 binding partner rod outer segment membrane protein 1 (ROM1) could serve as a phenotypic modifier. We utilized knockin and transgenic mouse models to evaluate the structural, functional, and biochemical effects of eliminating one allele of Rom1 (Rom1^+/−) in three different Prph2 models which mimic human disease: C213Y Prph2 (Prph2^C/+), K153Del Prph2 (Prph2^K/+) and R172W (Prph2^R172W). Reducing Rom1 in the absence of Prph2 mutations (Rom1^+/−) had no effect on retinal structure or function. However, the effects of reducing Rom1 in the presence of Prph2 mutations were highly variable. Prph2^K/+/Rom1^+/− mice had improved rod and cone function compared to Prph2^K/+ as well as amelioration of K153Del-associated defects in PRPH2/ROM1 oligomerization. In contrast, Prph2^R172W/Rom1^+/− animals had worsened rod and cone function and exacerbated retinal degeneration compared to Prph2^R172W animals. Removing one allele of Rom1 had no effect in Prph2^C/+. Combined, our findings support a role for non-pathogenic ROM1 null variants in contributing to phenotypic variability in mutant PRPH2-associated retinal degeneration. Since the effects of Rom1 reduction are variable, our data suggest that this contribution is specific to the type of Prph2 mutation.

中文翻译：

---

ROM1 有助于 PRPH2 相关视网膜疾病的表型异质性。

外周蛋白 2 (PRPH2) 是一种视网膜特异性四跨膜蛋白，对于杆状和锥状光感受器外段 (OS) 的形成至关重要。PRPH2突变的患者表现出严重的视网膜变性，其特征是巨大的家族间和家族内表型异质性。为了帮助理解这种突变内疾病变异的原因，我们询问 PRPH2 结合伴侣杆外段膜蛋白 1 (ROM1) 是否可以作为表型修饰符。我们利用敲入和转基因小鼠模型来评估在模拟人类疾病的三种不同Prph2模型中消除Rom1 的一个等位基因( Rom1 ^+/- )的结构、功能和生化效应：C213YPrph2 (Prph2 ^C/+ )、K153Del Prph2 (Prph2 ^K/+ )和 R172W ( Prph2 ^R172W )。在没有 Prph2 突变（Rom1 ^+/-）的情况下减少Rom1对视网膜结构或功能没有影响。然而，在存在Prph2突变的情况下减少Rom1的影响是高度可变的。Prph2 ^{K / +} / ROM1 ^+/-小鼠具有改善的杆和视锥功能相比Prph2 ^{K / +}以及在PRPH2 / ROM1低聚K153Del相关缺陷改善。相比之下，Prph2 ^R172W与Prph2 ^R172W动物相比，/Rom1 ^+/-动物的视杆和视锥功能恶化并加剧了视网膜变性。去除Rom1 的一个等位基因对Prph2 ^C/+没有影响。结合起来，我们的研究结果支持非致病性ROM1无效变异在导致突变型PRPH2相关视网膜变性的表型变异中的作用。由于Rom1减少的影响是可变的，我们的数据表明这种贡献特定于Prph2突变的类型。