Ovarian dysgenesis (OD), an XX disorder of sex development, presents with primary amenorrhea, hypergonadotrophic hypogonadism, and infertility. In an Ashkenazi Jewish patient with OD, whole exome sequencing identified compound heterozygous frameshifts in FIGNL1, a DNA damage response (DDR) gene: c.189del and c.1519_1523del. Chromosomal breakage was significantly increased in patient cells, both spontaneously, and following mitomycin C exposure. Transfection of DYK-tagged FIGNL1 constructs in HEK293 cells showed no detectable protein in FIGNL1c.189del and truncation with reduced expression in FIGNL1c.1519_1523del (64% of wild-type [WT], P = .003). FIGNL1 forms nuclear foci increased by phleomycin treatment (20.6 ± 1.6 vs 14.8 ± 2.4, P = .02). However, mutant constructs showed reduced DYK-FIGNL1 foci formation in non-treated cells (0.8 ± 0.9 and 5.6 ± 1.5 vs 14.8 ± 2.4 in DYK-FIGNL1WT, P < .001) and no increase with phleomycin treatment. In conclusion, FIGNL1 loss of function is a newly characterized OD gene, highlighting the DDR pathway's role in ovarian development and maintenance and suggesting chromosomal breakage as an assessment tool in XX-DSD patients.

中文翻译：

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DNA损伤反应基因FIGNL1的功能丧失会导致人类卵巢发育不全。

卵巢发育不全 (OD) 是一种性发育障碍，表现为原发性闭经、促性腺激素过多性腺功能减退症和不孕。在一名患有 OD 的德系犹太人患者中，全外显子组测序发现了 DNA 损伤反应 (DDR) 基因 FigNL1 中的复合杂合移码：c.189del 和 c.1519_1523del。患者细胞中的染色体断裂显着增加，无论是自发的还是暴露于丝裂霉素 C 后。HEK293 细胞中 DYK 标记的FigNL1 构建体的转染显示，FIGNL1c.189del 中没有可检测到的蛋白质，FIGNL1c.1519_1523del 中表达减少且截短（野生型 [WT] 的 64%，P = .003）。FigNL1 形成的核灶因腐草霉素处理而增加（20.6 ± 1.6 vs 14.8 ± 2.4，P = .02）。然而，突变体构建体在未处理的细胞中显示 DYK-FIGNL1 病灶形成减少（DYK-FIGNL1WT 中为 0.8 ± 0.9 和 5.6 ± 1.5 vs 14.8 ± 2.4，P < .001），并且用腐草霉素处理后没有增加。总之，FIGNL1 功能丧失是一个新鉴定的 OD 基因，强调了 DDR 通路在卵巢发育和维持中的作用，并表明染色体断裂可作为 XX-DSD 患者的评估工具。