YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases. We report 3 unrelated individuals with rare homozygous missense variants in who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in . We generated wild-type and variant genomic rescue constructs of the fly ortholog and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a allele to assess the expression pattern of Two individuals are homozygous for [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, developmental delay, and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for [NM_006555.3:c.191A>G p.(Tyr64Cys)] and exhibited neurodevelopmental disorders and optic atrophy. Fly is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type genomic rescue constructs can rescue the lethality and autophagic flux defects, whereas the variants are less efficient in rescuing the phenotypes. The variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).

中文翻译：

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YKT6 中的纯合错义变异会导致功能丧失，并与发育迟缓相关，伴或不伴严重婴儿肝病和肝细胞癌风险

YKT6 在多种细胞内囊泡运输事件中发挥重要作用，但与孟德尔疾病无关。我们报告了 3 名不相关的个​​体，他们具有罕见的纯合错义变异，他们表现出神经系统疾病，伴有或不伴有进行性婴儿肝病。我们在 中对变体进行了建模。我们生成了果蝇直系同源物的野生型和变异基因组拯救构建体，并比较了它们拯救突变果蝇功能丧失表型的能力。我们还生成了一个等位基因来评估两个个体的 [NM_006555.3:c.554A>G p.(Tyr185Cys)] 纯合子的表达模式，并表现出正常的产前过程，随后出现发育迟缓、发育迟缓和进行性肝病。单倍型分析确定了该变体侧翼的共享纯合区域，表明有共同的祖先。第三个人是 [NM_006555.3:c.191A>G p.(Tyr64Cys)] 纯合子，并表现出神经发育障碍和视神经萎缩。苍蝇是必需的，在脂肪体（类似于肝脏）和中枢神经系统中表达。野生型基因组拯救构建体可以拯救致死性和自噬流缺陷，而变体在拯救表型方面效率较低。这些变异是部分功能丧失的等位基因，p.(Tyr185Cys) 比 p.(Tyr64Cys) 更严重。