兽研摘要
蓝眼与有色被毛是家猫中备受追捧的特征。显性蓝眼（DBE）表型由PAX3基因突变引起，其特征为有色被毛背景下的蓝色眼睛。我们对文献的综述突出了四种DBE变体（DBE、DBE、DBE和DBE）的特征，强调了它们多样化的表型表达，包括蓝色眼睛和白色斑点以及跨猫品种的感觉神经性听力损失（SNHL）相关风险。我们还强调了因基因库有限而产生的品种特异性疾病，鉴于近亲繁殖的病理效应，并主张负责任的育种策略必须优先考虑遗传多样性以改善动物福利。由于DBE变体导致高幼猫死亡率，纯合变体预计会导致产前致死，杂合性与SNHL风险相关，因此在德国法律下继续使用该基因进行育种不能被视为合乎伦理。DBE、DBE和DBE杂合子猫尚未被证明表现出SNHL。我们试图对DBE变体对猫的影响进行分类，了解这是否与其他物种相当，并进一步解释眼睛颜色与SNHL之间的机制。
关键词：显性蓝眼（DBE）、PAX3、家猫、猫遗传学、感觉神经性听力损失、伴侣动物育种
通俗摘要
猫的蓝眼可能通过几种不同的遗传机制产生。虽然蓝眼通常与白色被毛或重点色模式相关，但也可能出现在完全有色的被毛中。这种特征被称为“显性蓝眼”（DBE）。目前已鉴定出几种影响配对盒3（PAX3）基因的DBE变体。其中一些变体还可能与听力损失或其他健康问题相关。本综述总结了目前关于猫蓝眼遗传学的知识，比较了DBE变体，并讨论了为何遗传检测、听力评估和负责任的育种决策对蓝眼猫至关重要。
引言
有观点认为眼睛颜色在野生物种中保持固定，但在家养物种如家猫中则更为多变，家猫通过育种暴露于不同的选择压力下[38]。事实上，猫品种的发展主要受人类对独特审美特征的偏好所塑造，包括眼睛颜色、被毛颜色以及图案[30,32,56]。被毛颜色已被证明会影响领养可能性[61]。David等人[11]在文献中鉴定了与蓝眼及其伴随特征相关的基因（伴有白色斑点），Lyons等人[33]在肢端色素沉着中进行了鉴定，以及在完全有色被毛中[2,3]。
鉴于人们对暹罗猫和布偶猫等品种中蓝眼猫的普遍热情，可以合理预期育种实践将继续纳入蓝眼特征。事实上，国际猫联合会（FIFé）最近的报告强调，“显性蓝眼”（DBE）特征[2,3]在有色被毛上的受欢迎程度不断上升，尤其是在缅因猫中（占FIFé签发血统证书的25%），以及在英国猫中，该特征被描述为“相当流行”[18]。像阿尔泰猫和托帕石猫这样明确选育最少白色斑点和醒目蓝眼的品种的建立，凸显了DBE表型日益增长的受欢迎程度[2,3]。然而，将审美目标与猫的健康相平衡至关重要，因为将外观置于福祉之上可能对纯种猫产生不利影响[24,36]。不幸的是，猫主人可能存在一种倾向，即主要基于审美特征而非长期健康来选择某些纯种猫[41]。
由于近亲繁殖实践降低了遗传多样性，这总体上会导致众多有害副作用，从产仔数减少和受孕并发症到免疫力受损和品种特异性疾病[4，15，24，31，63]。尽管历史上曾提出受控近亲繁殖作为一种策略来暴露有害隐性等位基因，以便将受影响的血系从繁育中移除，但这种方法在纯种猫中的实际适用性有限。繁育者很少有空闲空间或资源将整窝幼猫保留至成年以监测晚发性疾病。因此，在实践中，近亲繁殖更多用于巩固美学特征，而非系统性地清除疾病等位基因，这带来了在猫舍间传播新健康问题的重大风险。这种策略在分子遗传学时代之前可能更具合理性，当时没有实用工具在携带者产生受影响后代之前识别它们。具体例子包括家族性AA淀粉样变性、进行性视网膜萎缩，以及东方短毛猫及相关暹罗猫谱系中对纵隔淋巴瘤的易感性[16，17，34，53，60]。暹罗猫还受溶酶体贮积病影响，该病可导致神经和骨骼异常[9]。其他公认的例子包括曼岛猫中TBXT相关的脊柱异常、苏格兰折耳猫中TRPV4相关的骨软骨发育不良，以及蓝眼白猫的耳聋[5，8，20，22，24]。这为理解猫的繁育格局及随后的遗传特征提供了背景。由于施加的选择压力，品种特异性遗传疾病突显了在有限种群中必须采取平衡方法，并优先考虑伦理繁育实践[36]。
我们综述的重点是猫蓝眼的遗传基础，特别强调PAX3相关的DBE变异。我们旨在提供信息，以确保美学目标不损害猫的健康。我们的工作基于先前对PAX3 DBE变异（DBE、DBE、DBE和DBE）的遗传分析[1，2，3，44]。
蓝眼
黑素细胞是产生黑色素的细胞，因此参与毛皮和眼睛的色素沉着；它们也与内耳发育相关联[48]。在胚胎发生过程中，神经嵴来源的黑素母细胞迁移进入耳蜗并分化为血管纹的中间细胞群。这些细胞是正常血管纹成熟和维持内淋巴稳态所必需的，包括产生驱动毛细胞转导的耳蜗内电位；当黑素细胞迁移、存活或分化受到破坏时，血管纹失败，随后可发生耳蜗变性，导致听力损失[45，46，48]。因此，白猫，尤其是蓝眼白猫，有耳聋风险。猫繁育者必须使用脑干听觉诱发电反应（BAER）测试来检测其猫的听力，并避免繁育聋猫[21]。在此，我们进一步概述影响蓝眼的基因型和表型（以及猫中任何伴随的感觉神经性听力损失（SNHL）），讨论：（1）KIT原癌基因；（2）酪氨酸酶（TYR）基因，主要参与色素产生；（3）PAX3。我们在表1中对此进行了总结。
表1.
家猫蓝眼相关的遗传机制
KIT
猫的显性白色，也称为上位性白色，是由于KIT原癌基因上White位点存在至少一个显性W等位基因，该基因编码酪氨酸蛋白激酶KIT[11]。这可见于多个品种，如东方短毛猫、土耳其安哥拉猫、暹罗白猫（见图1A）和考曼尼猫。
[图表内容请查看原文]
David及其同事提出三个等位基因在白色色素沉着中起作用：显性白色（W）、白斑（ws）和野生型（w+）。当W存在时，该等位基因具有上位效应，完全外显，掩盖所有其他负责毛皮色素沉着的基因的表达。W等位基因的作用机制是干扰胚胎发育过程中黑素母细胞（黑素细胞前体细胞；负责产生黑色素色素）的迁移、增殖和/或存活。虹膜基质中存在此类色素是形成黄色、绿色或棕色眼睛色调的必要条件（结合光散射的丁达尔效应）[42，58]。因此，由于许多黑素细胞不能到达毛囊或在毛囊中发挥功能，这导致黑色素合成缺乏，进而导致完全白色的毛皮和极高的蓝眼可能性[11]。此外，David及其同事发现所有聋猫都携带至少一个W等位基因拷贝，所有W/W猫都表现出某种程度的SNHL；否则称为耳聋。
TYR
酪氨酸酶（TYR）基因主要参与色素生成，并编码酪氨酸酶——黑色素生成过程中的关键酶。该基因还驱动肢端黑化（重点色），常见于暹罗猫，这是哺乳动物中一种部分性、温度依赖性的白化形式（图1 B）[27]。TYR上C位点隐性等位基因（cs）的纯合状态编码一种热不稳定型酪氨酸酶，该酶在较低温度下活性最佳，因此在外周部位黑色素产量更高[33]。最终，这导致猫身体较冷部位（如口鼻部、爪部和耳部）色素沉着更深。C位点的等位基因状态也决定眼睛颜色；在cs/cs基因型的猫中，酪氨酸酶的热不稳定性导致虹膜基质（身体较温暖区域，酶功能降低）中黑色素合成显著减少或完全缺失。与通过黑色素细胞迁移缺失起作用的W等位基因不同，该表型源于眼内基质色素沉着的缺失[33]。这种色素缺乏导致眼睛的可见颜色完全由丁达尔效应决定：光线在基质胶体结构上的散射[42, 58]。短波光（蓝色、浅蓝色）散射更为强烈，使眼睛呈现重点色猫典型的特征性蓝色。布偶猫因该C位点基因型而具有蓝眼，有时由于面部和腿部的双色和手套图案而“暹罗”表型不太明显[33]。白色暹罗型猫如Foreign White同时携带cs/cs和显性白色等位基因W，后者掩盖了重点色图案但保留了蓝眼。与cs不同（cs与耳聋无关），W等位基因是白猫先天性感音神经性耳聋的已知风险因素[10, 22, 52]。为完整起见，我们注意到蓝眼也可出现在C位点的白化系列中。白化系列包括TYR的隐性功能丧失等位基因（如c和ca），这些等位基因严重降低酪氨酸酶活性，从而减少被毛和眼睛中的色素生成。除cs（暹罗/重点色）外，一种非常罕见的蓝眼白化等位基因（ca）产生完全白色的被毛和因基质色素缺失（即丁达尔散射）而呈淡半透明蓝色的虹膜，且与耳聋无关[27, 57]。
总之，重点色毛色由纯合cs等位基因控制，蓝眼表型归因于酶活性缺失。相比之下，白毛蓝眼猫携带至少一个拷贝的显性W等位基因（意味着色素不能沉积到毛发和眼睛中）。因此，在大部分遗传史中，猫的蓝眼与重点色相关，如暹罗猫或其他白毛猫。
PAX3
PAX3 DBE变异是指导致家猫有色被毛上蓝眼的变异（见图2）。猫中所有已知形式的DBE突变均为显性，意味着猫只需遗传一个拷贝的突变基因即可表达该性状。截至2025年，已描述四种PAX3 DBE等位基因：DBE(Celestial)、DBE(Rociri Elvis)、DBE(Altai)和新报道的DBE(Agostino)。这些等位基因在蓝色虹膜的外显率和白色斑点的范围上存在差异。也可观察到不完全外显，即不出现蓝眼；相反，一些幼猫在婴儿期表现“红眼效应”，即在某些光照条件下眼睛呈现红色反光。在这种情况下，猫被标记为“潜伏DBE携带者”。潜伏DBE携带者已在DBE和DBE品系中描述，最近也在DBE缅因猫谱系中有所描述[1]。DBE变异还携带不同程度的SNHL风险[1, 2, 3, 44]。
[图表内容请查看原文]
DBE（Altai显性蓝眼）由PAX3内含子4中的RD-114长末端重复序列（LTR）插入驱动。DBE是首个选择性繁育的DBE变异，分离自Fyodor的奠基谱系，Fyodor是一只发现于哈萨克斯坦阿尔泰山脉的全色蓝眼猫。该基因现已传播至其他地区，包括俄罗斯和乌克兰，在那里被引入多个选育计划，包括建立“Seymour”。1984年，类似突变在新墨西哥州被正式确认，导致Ojos Azules品种的创建。然而，由于患病猫骨骼畸形发生率高，Ojos Azules的繁育计划已停止[3]。DBE也已在一些源自Seymour猫的英国和波斯品种中发现，提示存在共同祖先[3]。该变异也与蓝眼和极少的白色斑点相关。纯合猫可存活但可能出现耳聋。在Abitbol等人[3]报道的队列中，杂合DBE猫未显示BAER确认的耳聋。
DBE（Celestial显性蓝眼）源于内源性逆转录病毒LTR（一种逆转录病毒调控序列）插入PAX3内含子4。该变异源自品种奠基者Roxy，以极少/多变的白色斑点图案和亮蓝色眼睛为特征。杂合子中不存在SNHL。然而——可能由于胚胎期黑色素细胞迁移改变——纯合子中可能发生SNHL[3]。
DBE（Rociri Elvis显性蓝眼），在一个荷兰缅因猫品系中于PAX3基因中发现，由该基因c.937 C > T突变所致[44]。特征性蓝眼常伴有白斑，有时伴有耳聋（见表2）。在Rociri Elvis品系中，该突变还导致幼猫高死亡率。DBE表现为常染色体显性遗传性状，一个突变拷贝即可导致DBE，并在初始家系中高比例的患病猫中与耳聋相关。Rudd Garces等人[44]预测，该变异的两个拷贝可能导致产前死亡。由于这些病理效应以及纯合个体可能无法存活，动物遗传学中心建议不要繁育携带DBE的猫[23]。然而，更近期的BAER数据显示，同一血统的一些DBE猫听力正常，并且存在无蓝色虹膜的潜伏DBE携带者，表明外显率可变，且遗传背景可能影响耳聋的表达[1]。该性状与Waardenburg综合征相似，后者是人类的一种听觉-色素性疾病，由常染色体显性PAX3变异引起[25, 35, 44]。
已知与家猫显性蓝眼（DBE）表型相关的猫PAX3基因独立突变。该表总结了四个已识别DBE等位基因的变异命名、基因组位置和分子细节，突出显示了它们的不同来源及其对PAX3功能的影响[3]。LTR：长末端重复序列
DBE（Agostino显性蓝眼）对应于在一个缅因猫谱系（Agostino系）中报道的PAX3：外显子2的c.160del移码突变。来自该品系的所有DBE猫经基因分型均为该缺失的杂合子，而相关的非DBE猫和对照猫为野生型，这与常染色体显性遗传和强基因型-表型相关性一致。在可获得的Agostino病例中未报告BAER确认的耳聋；然而，BAER数据仍然有限，需要进一步检测以确定患病率。在当前数据集中，Agostino品系中未识别出潜伏猫[1]。
该领域的现状
现代繁育的挑战包括管理近亲繁殖的风险或受控引入新的遗传性状。品种中遗传负荷的积累与遗传病风险增加和免疫系统减弱直接相关[36]。
分子技术的作用已被用于实现对繁育计划的负责任管理，并改进对家畜遗传结局的预测[6, 47]。鉴定负责从抗病性到外观等广泛性状的基因，使得可以引入一种方法，使繁育者能够从直觉或纯表型选择方法转向伦理上明智的选择[19]。目前，蓝眼等性状可能被随意引入。因此，对蓝眼猫进行PAX3变异检测可识别产生有健康问题幼猫的风险；遗传谱分析将使背景血统信息可供繁育者参考。这还将使猫主人若想让其交配时，能够了解幼猫是否可能患有缺陷。正如我们所知，SNHL可伴随DBE，因此识别基因和表型对于知情繁育至关重要。鉴于德国《动物福利法》禁止繁育有听力缺陷的动物，这一点尤其相关[44]。
还应注意，在繁育决策中使用遗传信息可能受到检测成本和可及性的影响，因为特定变异的检测可及性可能因国家和实验室而异。
讨论
KIT、TYR和PAX3基因与猫的蓝眼有关。在PAX3相关DBE变异的情况下，猫也可表现为蓝眼而无白色被毛或重点色图案。如前所述，目前记录了四种PAX3 DBE变异（DBE、DBE、DBE、DBE），其蓝眼和白斑的表现度不同，SNHL风险可变。
在德国和奥地利，根据德国《动物福利法》第11b条和奥地利《动物福利法》第5(2)条，“如果可预见后代将因遗传状况而遭受疼痛、痛苦、伤害或恐惧，则禁止繁育。这包括耳聋等状况”[44]。在英国（U.K.）和美国（U.S.A.），猫受1951年《宠物动物法》（U.K.）和《动物福利法》（U.S.A.）管辖，这些法律未规定猫繁育中遗传健康的重要性。FIFé是猫 Congress 九个成员之一，旨在改善猫的健康和福利。尽管有法律、法规和协会，全球猫福利的责任仍落在繁育者和主人手中。
目前正努力减少已确立宠物品种的健康问题并扩大其基因库。例如，拉布拉多犬和德国牧羊犬易患髋关节发育不良，皇家兽医学院与养犬俱乐部之间的一项倡议——BVA/KC髋关节发育不良筛查计划——已被引入，旨在为犬主提供关于髋关节发育不良存在情况的信息以及后续适当的繁殖选择建议[7，43]。在猫中，“RUS4Osh”是一个经FIFé批准的欧洲项目，该项目将东方短毛猫与俄罗斯蓝猫进行异系交配。尽管俄罗斯蓝猫通常被认为是一个健康的品种，但它们可能易患先天性白内障，这在猫科动物中较为罕见[39]。RUS4Osh提出，引入具有更广泛遗传基础的杂交健康个体将使品种得以延续，而不仅仅是为了追求赛级获胜性状。此类项目需要细致谨慎的方法，且仅在严格控制的措施下进行。就PAX3等基因而言，目前识别DBE性状能否在伦理标准内维持的空间有限。FIFé规定，两只白猫不得交配，因为存在健康风险。此外，由于DBE突变即使在杂合状态下也可能存在SNHL的能力，在繁殖池中延续该性状不符合德国法律，也不符合FIFé指南的要求。在Agostino（DBE）缅因猫血系中，繁育者未报告耳聋病例，但未进行BAER检测[1]。目前，DBE及DBE杂合子与耳聋并无关联[3]。
在考虑其他物种中SNHL与色素的关系时，文献较为零散。研究者使用模型进行了详尽研究以鉴定小鼠中与听力损失相关的基因，再次确定PAX3为致病基因之一[49]。色素表型也在犬中被探索，特别是边境牧羊犬，显示白色毛发、蓝色虹膜与SNHL之间存在关联[12，40]，然而，遗传连锁关系尚未确立。
对于智人而言，尽管蓝眼由黑色素细胞迁移驱动，但其根本驱动因素位于15号染色体的OCA2-HERC2位点[54，55]。人类可能拥有蓝眼而无论肤色深浅，且尽管较浅的眼色影响噪声性听力损失的易感性，但单独并不与SNHL相关联[37]。然而，在发育障碍中，如Prader-Willi综合征（PWS）和Angelman综合征（AS），个体常表现白色皮肤和毛发以及蓝色眼睛[28]。这些最初也被认为由15号染色体上的OCA2-HERC2驱动，但15号染色体上的另一个基因GABRB3（15q11-q13）似乎驱动了这些个体的眼部色素减退[13]。有人提出HERC2可能具有一个调控组件，进而抑制OCA2的表达[14]。Waardenburg综合征也与PAX3相关，约半数携带PAX3突变的患者有听力损失，可能由于内耳形态发生异常所致[25，51]。小鼠研究进一步证明了PAX3对黑色素细胞发育和内耳存活的重要性[29，59]。此外，一种Waardenburg小鼠突变体被发现不表达SNHL，对耳蜗发育无影响，提示该基因在小鼠中的其他区域可能允许内耳结构的挽救[51]。这些研究者还鉴定了酪氨酸酶相关蛋白2（TRP2），一种神经嵴细胞标记基因，其突变对分化和迁移无影响，但影响黑色素母细胞的存活和靶向[50]。
由于哺乳动物耳聋的生理学已通过黑色素细胞缺乏导致血管纹功能障碍（因内耳电位缺失）而被定义[48]，我们不禁要问，色素缺乏而不伴耳聋是如何可能的。这是否可能由于挽救性突变，如斑块突变体[51]或存活因子[50]在发育的某一时间点导致调控开关？在视网膜疾病中已确立导致较轻疾病的亚效等位基因，可保护视觉功能[26，62]——迄今为止，尚不清楚PAX3在黑色素细胞迁移中是否存在这种情况。
因此，跨物种而言，色素与SNHL之间的关联是复杂的。在猫中，应进一步了解关于外显率的遗传信息，以及某些DBE变异如何在杂合形式下表现出无SNHL的表型。这可以通过从其他物种中汲取平行经验来实现，无论PAX3变异是否可能以亚效等位基因形式存在，以及加深对黑色素细胞迁移的理解。最终，我们尚不清楚在有色被毛上建立蓝眼表型是否可能不伴随一定程度的听力风险。
结论
本综述强调了猫蓝眼的遗传学，并讨论了由PAX3基因不同突变引起的DBE性状[3]。鉴于我们对黑色素细胞迁移如何影响色素沉着和听力的理解，我们建议需要进一步了解SNHL为何不在DBE及DBE杂合子中出现。拥有蓝眼猫的人可能选择繁殖它们而不考虑遗传背景。鉴于不同DBE变异的潜在健康影响，我们希望本文能引起一定程度的警惕。
作者贡献
O.S.撰写了初稿。随后由V.S.F.和E.C.进行完善和编辑。V.S.F.提供了学术意见和指导支持。所有作者审阅了稿件。
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Abstract
Blue eyes and a colored coat are a sought-after trait in Felis catus . The dominant blue eye (DBE) phenotype arises from mutations within the PAX3 gene and is characterized by blue eyes on the background of a colored coat. Our review of the literature highlights the characteristics of four DBE variants, DBE, DBE, DBE and DBE, emphasizing their diverse phenotypic expressions, including blue eye color and white spotting to associated risks of sensorineural hearing loss (SNHL) across cat breeds. We also highlight breed-specific disorders arising from limited gene pools, and given pathological effects of inbreeding and posit that responsible breeding strategies must prioritize genetic diversity to improve animal welfare. As DBE variants resulted in high kitten mortality, with homozygous variants predicted to result in prenatal lethality and heterozygosity associated with a risk of SNHL and continuing to breed with this gene cannot be considered ethical under German Law. DBE, DBE and DBE heterozygote felines have not yet been shown to exhibit SNHL. We sought to categorize DBE variant effects on cats, understand if this is comparable to other species and explain further the mechanism between eye color and SNHL.
Keywords: Dominant blue eyes (DBE), PAX3, Felis catus, Feline genetics, Sensorineural hearing loss, Companion animal breeding
Lay summary
Blue eyes in cats may arise through several different genetic mechanisms. Whilst blue eyes are commonly associated with white coats or colorpoint patterns, this can also occur with a fully colored coat. This is a trait referred to as “dominant blue eyes” (DBE). Several DBE variants affecting the paired box 3 (PAX3) gene have now been identified. Some of these variants may also be associated with hearing loss or other health concerns. This review summarizes current knowledge of the genetics of blue eyes in cats, compares DBE variants, and discusses why genetic testing, hearing assessment, and responsible breeding decisions are important when it comes to cats with blue eyes.
Introduction
Eye color has been proposed to remain fixed in wild species, yet to be more variable in domestic species such as Felis catus , which has been exposed to different selection pressures through breeding [ 38 ]. Indeed, the development of cat breeds has been predominantly shaped by human preferences for distinctive aesthetic traits, including eye color and coat color, as well as pattern [ 30 , 32 , 56 ]. Coat color has been shown to influence adoptability [ 61 ]. Genes contributing to blue eyes and their accompanying traits have been identified in the literature by David et al. [ 11 ] with white spotting, Lyons et al. [ 33 ] in acromelanism and, in fully colored coats [ 2 , 3 ].
Given the general enthusiasm for blue-eyed cats in breeds like the Siamese and Ragdoll, it is reasonable to anticipate that breeding practices will continue to incorporate blue eyes. Indeed, recent reports from the Fédération Internationale Féline (FIFé) highlight the rising popularity of the “dominant blue eye” (DBE) trait [ 2 , 3 ] on a colored coat, particularly in Maine Coons, which account for 25% of FIFé-issued pedigrees, and British cats, where the trait is described as “quite in trend” [ 18 ]. The establishment of breeds like Altai and Topaz selected explicitly for minimal white spotting and striking blue eyes underscores the increasing popularity of the DBE phenotype [ 2 , 3 ]. However, it is critical to balance aesthetic objectives with feline health, as the prioritization of appearance over well-being can have detrimental effects on purebred cats [ 24 , 36 ]. Unfortunately, there can be a tendency of cat owners to select certain pedigree cats predominantly based on aesthetic features as a priority over long-term health [ 41 ].
As inbreeding practices decrease genetic diversity, this leads to numerous detrimental side effects overall, ranging from decreased litter size and conception complications to compromised immunity and breed-specific disorders [ 4 , 15 , 24 , 31 , 63 ]. Although controlled inbreeding has historically been proposed as a strategy to expose deleterious recessive alleles so that affected lines can be removed from breeding, this approach has limited practical applicability in pedigree cats. Breeders rarely have the space or resources to retain entire litters to adulthood in order to monitor late-onset disease. In practice, inbreeding is therefore more often employed to consolidate aesthetic traits than to systematically purge disease alleles, which carries a substantial risk of disseminating novel health problems across catteries. Such a strategy may have been more defensible in the pre-molecular genetics era, when no practical tools were available to identify carriers before they produced affected offspring. Specific examples include familial AA amyloidosis, progressive retinal atrophy, and a predisposition to mediastinal lymphoma in Oriental Shorthair and related Siamese lineages [ 16 , 17 , 34 , 53 , 60 ]. Siamese cats are also affected by lysosomal storage disease, which can result in neurological and skeletal abnormalities [ 9 ]. Other well-established examples include TBXT-associated spinal abnormalities in Manx cats, TRPV4-associated osteochondrodysplasia in Scottish Fold cats, and deafness in blue-eyed white cats [ 5 , 8 , 20 , 22 , 24 ]. This provides the context for understanding the landscape of breeding and subsequent genetic traits in cats. Breed-specific genetic disorders, owing to imposed selection pressures, highlight that balanced approaches must be taken in limited populations with the prioritization of ethical breeding practices [ 36 ].
The focus of our review is on the genetic basis of blue eyes in cats, with a particular emphasis on PAX3-associated DBE variants. We aim to provide information towards ensuring that aesthetic goals do not compromise feline health. Our work is informed by previous genetic analyses on PAX3 DBE variants (DBE, DBE, DBE and DBE) [ 1 , 2 , 3 , 44 ].
Blue eyes
Melanocytes are melanin-producing cells and, as such, are involved in fur and eye pigmentation; they are also coupled with inner ear development [ 48 ]. During embryogenesis, neural crest–derived melanoblasts migrate into the cochlea and differentiate into the intermediate-cell population of the stria vascularis. These cells are required for normal strial maturation and for maintaining endolymph homeostasis, including generation of the endocochlear potential that drives hair-cell transduction; when melanocyte migration, survival, or differentiation is disrupted, the stria fails and cochlear degeneration can follow, resulting in hearing loss [ 45 , 46 , 48 ]. Therefore, white cats, especially those with blue eyes, are at risk for deafness. Cat breeders must use the brainstem auditory evoked response (BAER) test to test the hearing of their cats and avoid breeding deaf animals [ 21 ]. Here we provide a further overview of the genotypes and phenotypes influencing blue eyes (and any accompanying sensorineural hearing loss (SNHL) in cats, discussing: (1) the KIT proto-oncogene; (2) the tyrosinase (TYR) gene, which is predominantly involved in pigment production and (3) PAX3. We have summarized this in Table 1 .
Table 1.
Genetic mechanisms associated with blue eyes in domestic cats
KIT
Dominant white color in cats, also known as epistatic white, is due to the presence of at least one dominant W allele in the White locus on the KIT proto-oncogene, which encodes the tyrosine-protein kinase KIT [ 11 ]. This can be seen in several breeds, such as the Oriental Shorthair, Turkish Angora, Siamese White (see Fig. 1 A) and Khao Manee.
[图表内容请查看原文]
Three alleles were proposed by David and colleagues to play a role in white pigmentation: the dominant white (W), white spotting (ws) and wild-type (w+). When W is present, the allele has an epistatic effect, with complete penetrance, masking the expression of all other genes responsible for coat pigmentation. The mechanism of action of the W allele is to interfere with the migration, proliferation, and/or survival of melanoblasts (melanocyte precursor cells; responsible for producing the melanin pigment) during embryonic development. The presence of such pigments in the stroma of the iris is a necessary condition for the formation of yellow, green, or brown eye shades (in combination with the Tyndall effect of light scattering) [ 42 , 58 ]. Therefore, as a number of melanocytes do not reach or function in the hair follicles, this results in a lack of melanin synthesis and, in turn, a completely white coat and a very high likelihood of blue eyes [ 11 ]. In addition, David and colleagues found all deaf cats to be carrying at least one copy of the W allele and all W/W cats displayed some degree of SNHL; otherwise referred to as deafness.
TYR
The tyrosinase (TYR) gene is predominantly involved in pigment production and encodes the tyrosinase enzyme – a key enzyme in melanogenesis. This gene also drives acromelanism (colorpoint), often seen in the Siamese cat, a form of partial, temperature-dependent albinism in mammals (Fig. 1 B) [ 27 ]. A homozygous state for the recessive allele (cs) of the C locus on TYR encodes a thermolabile form of tyrosinase, where the activity of this enzyme is optimal at lower temperatures, hence higher production of melanin in the peripheries [ 33 ]. Ultimately, this results in darker pigmentation at colder parts of a cat’s body, e.g., snout, paws and ears. The allelic state of the C locus also determines eye color; in cats with the cs/cs genotype, the thermolability of tyrosinase leads to a significant decrease or complete absence of melanin synthesis in the stroma of the iris (a warmer region of the body where enzyme function is decreased). Unlike the W allele, which operates through a lack of melanocyte migration, this phenotype is therefore derived from a lack of stromal pigmentation in the eyes [ 33 ]. This lack of pigment results in the visible color of the eyes being determined exclusively by the Tyndall effect: a scattering of light on the colloidal structures of the stroma [ 42 , 58 ]. Short-wave light (blue, light blue) is scattered more intensely, which gives the eyes the characteristic blue color typical of colorpoint cats. Ragdolls have blue eyes due to this C-locus genotype, sometimes with a less prominent “Siamese” phenotype due to bicolored and mitted patterns on the face and legs [ 33 ]. White Siamese-type cats such as Foreign White carry both cs/cs and the dominant white allele W, which masks the point pattern but leaves the blue eyes. In contrast to cs, which is not associated with deafness, the W allele is a well-known risk factor for congenital sensorineural deafness in white cats [ 10 , 22 , 52 ]. For completeness, we note that blue eyes can also occur in the albino series at the C locus. The albino series comprises recessive loss-of-function alleles of TYR (such as c and ca.) that severely reduce tyrosinase activity and, consequently, pigment production in the coat and eyes. In addition to cs (Siamese/colorpoint), a very rare blue-eyed albino allele (ca.) produces a fully white coat with pale translucent blue irises due to absent stromal pigment (i.e., Tyndall scattering), and is not associated with deafness [ 27 , 57 ].
To conclude, colorpoint coloration is controlled by a homozygous cs allele, with the blue eye phenotype due to lacking enzyme activity. Comparatively, white-haired blue-eyed cats carry at least a single copy of the dominant W allele (meaning a lack of deposition of pigment into hair and eyes). Therefore, throughout most of the genetic history, blue eyes in cats were associated with color points, such as Siamese or other white-haired cats.
PAX3
PAX3 DBE variants refer to the variants responsible for blue eyes on a colored coat in domestic cats ( see Fig. 2 ). All known forms of the DBE mutation in cats are dominant, meaning that a cat only needs to inherit one copy of the altered gene to express the trait. As of 2025, four PAX3 DBE alleles have been described: DBE(Celestial), DBE(Rociri Elvis), DBE(Altai), and the newly reported DBE (Agostino). These alleles differ in their expressivity for blue irides and extent of white spotting. Incomplete penetrance can also be seen, where blue eyes do not occur; instead, some kittens show a “red eye effect” during infancy, in which the eyes display a reddish reflection under certain lighting conditions. In such instances, cats are labeled “latent DBE carriers”. Latent DBE carriers have been described in DBE and DBE lines, and more recently also in the DBE Maine Coon lineage [ 1 ]. DBE variants also carry a varying risk of SNHL [ 1 , 2 , 3 , 44 ].
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DBE (Altai Dominant Blue Eye) is driven by an RD-114 long terminal repeat (LTR) insertion in intron 4 of PAX3. DBE was the first selectively bred DBE variant, isolated from a founding lineage of Fyodor, a full-color blue-eyed cat found in the Altai Mountains of Kazakhstan. This gene has now spread to other regions, including Russia and Ukraine, where it was inducted into several selection programs including the establishment of “Seymour”. In 1984, a similar mutation was officially recognized in New Mexico, leading to the creation of the Ojos Azules breed. However, breeding programs for the Ojos Azules were discontinued due to the high incidence of skeletal deformities in affected cats [ 3 ]. DBE has also been found in some British and Persian breeds descended from the Seymour cat suggesting a common ancestor [ 3 ]. This variant is also associated with blue eyes and minimal white spotting. Homozygous cats are viable but may exhibit deafness. In the cohorts reported by Abitbol et al., [ 3 ], heterozygous DBE cats did not show BAER-confirmed deafness.
DBE (Celestial Dominant Blue Eyes) arises from the insertion of an endogenous retroviral LTR, a retroviral regulatory sequence, into intron 4 of PAX3. The variant, derived from the breed’s founder, Roxy, is distinguished by minimal/variable white spotting patterns and bright blue eyes. SNHL is not present in heterozygotes. However — likely due to altered embryonic melanocyte migration — SNHL may occur in homozygotes [ 3 ].
DBE (Rociri Elvis Dominant Blue Eyes), identified in a Dutch line of Maine Coons in PAX3 due to a c.937 C > T mutation in the gene [ 44 ]. The characteristic blue eyes were often accompanied by white spots and sometimes deafness (see Table 2 ). In the Rociri Elvis line, this mutation also resulted in high kitten mortality. DBE behaves as an autosomal dominant trait, with one copy of the mutation causing DBE and being associated with deafness in a high proportion of affected cats in the initial family. Rudd Garces et al., [ 44 ] predicted two copies of this variant would likely to result in prenatal mortality. Due to these pathological effects and the likely non-viability of homozygous individuals, the Center for Animal Genetics, advises against breeding cats carrying DBE [ 23 ]. More recent BAER data, however, show that some DBE cats from the same lineage have normal hearing and that latent DBE carriers without blue irides also exist, indicating variable penetrance and a likely influence of genetic background on the expression of deafness [ 1 ]. This trait parallels with Waardenburg syndrome, an auditory-pigmentary disorder in humans, arising from an autosomal dominant PAX3 variant [ 25 , 35 , 44 ].
Known independent mutations in the feline PAX3 gene associated with the Dominant Blue Eyes (DBE) phenotype in domestic cats. The table summarizes the variant nomenclature, genomic locations, and molecular details of the four identified DBE alleles, highlighting their distinct origins and effects on PAX3 function [ 3 ]. LTR: long terminal repeat
DBE (Agostino Dominant Blue Eyes) corresponds to a PAX3:c.160del frameshift in exon 2 reported in a Maine Coon lineage (Agostino line). All DBE cats genotyped from this line were heterozygous for the deletion, whereas related non-DBE and control cats were wild-type, consistent with autosomal dominant inheritance and strong genotype–phenotype correlation. No BAER-confirmed deafness was reported in the available Agostino cases; however, BAER data remain limited and further testing is needed to establish prevalence. Latent cats were not identified in the Agostino line in the current dataset [ 1 ].
Current status of the field
The challenges of modern breeding include managing the risks of inbreeding or the controlled introduction of new genetic traits. An accumulation in genetic load in the breed directly correlates with an increased risk of hereditary diseases and a weakened immune system [ 36 ].
The role of molecular technologies has been utilized in allowing responsible management of programs and improved prediction of the genetic outcomes regarding livestock [ 6 , 47 ]. This identification of genes responsible for a wide range of traits, from disease resistance to appearance allows the introduction of an approach where breeders can move from intuitive or purely phenotypic selection methods to ethically informed choices [ 19 ]. Currently, traits like blue eyes may be introduced haphazardly. Therefore, testing for PAX3 variants in blue-eyed cats identifies the risk of producing kittens with health issues; genetic profiling would allow for a background ancestry to inform breeders. This also would allow for cat owners to have some insight into whether kittens may suffer from defects should they want to mate them. As we know, SNHL can accompany DBE, it is critical for informed breeding to identify the gene and phenotype. This is especially relevant given the ban on breeding animals with hearing defects under the German Animal Welfare Act [ 44 ].
It should also be noted that the use of genetic information in breeding decisions may be influenced by the cost and availability of testing, as access to tests for specific variants can vary between countries and laboratories.
Discussion
KIT, TYR and PAX3 genes contribute to blue eyes in cats. In the case of PAX3-associated DBE variants, cats can also present with blue eyes without a white coat or a colorpoint pattern. As mentioned throughout, four PAX3 DBE variants are now documented (DBE, DBE, DBE, DBE), with differing expressivity for blue eyes and white spotting and variable risk of SNHL.
In Germany and Austria, “ breeding is prohibited if it is foreseeable that the offspring will suffer from pain , suffering , injury , or fear due to hereditary conditions. This includes conditions such as deafness ” under Article 11b of the German Animal Welfare Act and 5(2) of the Austrian Animal Welfare Act, [ 44 ]. In the United Kingdom (U.K.) and the United States of America (U.S.A.), cats fall under the Pet Animals Act 1951 (U.K.) and the Animal Welfare Act (U.S.A.), laws which do not stipulate the importance of genetic health in cat breeding. FIFé, one of the nine members of the Cat Congress, aims to improve the health and welfare of cats. Despite laws, regulations and associations, responsibility for feline wellbeing globally falls to the hands of breeders and owners.
Efforts are being made to reduce health issues and widen the gene pool in established pet breeds. For example, Labrador and German Shepherd dogs are predisposed to hip dysplasia, and an initiative between the Royal Veterinary College and Kennel Club; BVA/KC Hip Dysplasia Screening Scheme has been introduced to provide owners with information on the presence of hip dysplasia and subsequent appropriate breeding choices [ 7 , 43 ]. In cats, “RUS4Osh” is a FIFé-approved European project in which Oriental Shorthairs are outcrossed with Russian Blues. Although Russian Blue cats are generally considered a healthy breed, they may be prone to congenital cataracts, which are rare amongst felines [ 39 ]. RUS4Osh proposes that introducing healthy hybrids with a broader genetic base will allow for the longevity of breeds rather than just show-winning traits. Such projects require a meticulous and careful approach, and only under strictly controlled measures. With genes such as PAX3, there is currently limited scope to identify whether the DBE trait can be maintained within ethical standards. FIFé states that two white cats cannot be bred due to health risks. Furthermore, as the DBE mutation possesses the ability for SNHL to be present even in heterozygous states, continuation of this trait in the breeding pool does not adhere to German Law, nor is it acceptable under FIFé guidelines. In the Agostino (DBE) Maine Coon line, no deafness was reported by breeders, but no BAER testing was performed [ 1 ]. At this point in time DBE and DBE heterozygotes are not associated with deafness [ 3 ].
When considering the relationship of SNHL and pigment in other species, there is a scattering of the literature. Thorough research using models was performed to identify genes related to hearing loss in mice, again identifying PAX3 as one of the causants [ 49 ]. Pigment phenotype was also explored in dogs, specifically the Border Collie, showing an association between white hair, blue iris and SNHL [ 12 , 40 ], however, genetic linkage was not established.
For Homo sapiens , although blue eyes are driven by melanocyte migration, the underpinning driver is at the OCA2-HERC2 locus of chromosome 15 [ 54 , 55 ]. It is possible for humans to have blue eyes with or without light skin and although lighter eye color influences proclivity to noise-induced hearing loss, it is not linked to SNHL alone [ 37 ]. However, in developmental disorders, such as Prader-Willi syndrome (PWS) and Angelman syndrome (AS), individuals often express white skin and hair as well as blue eyes [ 28 ]. These were initially also believed to be driven by OCA2-HERC2 on chromosome 15, but another gene on chromosome 15, GABRB3 (15q11-q13) appears to drive ocular hypopigmentation in these individuals [ 13 ]. It has been proposed that HERC2 may possess a regulatory component that, in turn, inhibits expression of OCA2 [ 14 ]. Waardenburg syndrome is also PAX3-associated, and around half of patients with the PAX3 mutation have hearing loss, likely due to abnormalities in inner ear morphogenesis [ 25 , 51 ]. Mouse studies have further demonstrated the importance of PAX3 for melanocyte development and survival in the inner ear [ 29 , 59 ]. Furthermore, a mouse mutant of Waardenburg was found not to express SNHL, with no impacts on cochlear development, suggesting other regions of this gene in mice may allow for rescue of inner ear structure [ 51 ]. These researchers also identified tyrosinase-related protein 2 (TRP2), a neural crest cell marker gene, where mutation resulted in no impacts on differentiation and migration, but an influence on melanoblast survival and targeting [ 50 ].
As the physiology of deafness in mammals has been defined through the lack of melanocytes causing strial dysfunction through absent endocochlear potential [ 48 ], we ask how it is possible for a lack of pigment to be present without deafness. Could this be due to a rescue mutation, such as in the blotch mutant [ 51 ] or a survival factor [ 50 ] resulting in a regulatory switch at a certain time point in development? Hypomorphic alleles resulting in milder disease have been established in retinal disease, which allows for preservation of visual function [ 26 , 62 ] – as of yet, it is not known if this can exist for PAX3 in migration of melanocytes.
Therefore, across species, the association between pigment and SNHL is complex. In cats, further genetic information on penetrance and indeed how certain DBE variants can exhibit a phenotype absent of SNHL in the heterozygous form should be further understood. This could be achieved through parallels drawn from other species, whether PAX3 variants could exist as hypomorphic alleles and a deepened understanding of melanocyte migration. Ultimately, we do not yet know if a blue-eyed phenotype on a colored coat is possible to establish without some degree of hearing risk.
Conclusion
This review highlights the genetics of blue eyes in cats and discusses the DBE trait arising from differing mutations in the PAX3 gene [ 3 ]. Given our understanding of how melanocyte migration influences both pigmentation and hearing, we suggest further understanding of how SNHL does not arise in DBE and DBE heterozygotes is required. Those who own cats with blue eyes may choose to breed them without consideration of genetic background. Given the potential health impacts of different DBE variants, we hope for this manuscript to stimulate a degree of caution.
Author contributions
O.S. wrote the initial manuscript. This was later developed and edited by V.S.F. and E.C. V.S.F. provided intellectual input and supervisory support. All authors reviewed the manuscript.
Funding
None.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethical approval
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
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