A case of 46,XY disorders of sex development with congenital heart disease caused by a GATA4 variant

IF 1.3 4区 医学 Q3 PEDIATRICS
Yui Shichiri, Yoshimi Kato, Hidehito Inagaki, Takema Kato, Naoko Ishihara, Masafumi Miyata, Hiroko Boda, Arisa Kojima, Misa Miyake, Hiroki Kurahashi
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引用次数: 3

Abstract

GATA4 is known to be a causative gene for congenital heart disease, but has also now been associated with disorders of sexual development (DSD). We here report a pathogenic variant of GATA4 in a 46,XY DSD patient with an atrial septal defect, identified by whole-exome sequencing to be c.487C>T (p.Pro163Ser). This mutation resulted in reduced transcriptional activity of the downstream gene. When we compared this transcriptional activity level with other GATA4 variants, those that had been identified in patients with cardiac defects and DSD showed less activity than those in patients with cardiac defect only. This suggests that the normal development of the heart requires more strict regulation of GATA4 transcription than testicular development. Further, when the different variants were co-expressed with wild-type, the transcriptional activities were consistently lower than would be expected from an additive effect, suggesting a dominant-negative impact of the variant via dimer formation of the GATA4 protein. Since these pathogenic GATA4 variants are occasionally identified in healthy parents, a threshold model of quantitative traits may explain the cardiac defect or DSD phenotypes that they cause.

46,xy性发育障碍合并先天性心脏病由GATA4变异引起1例
众所周知,GATA4是先天性心脏病的致病基因,但现在也与性发育障碍(DSD)有关。我们在此报告了一例46,xy房间隔缺损DSD患者中GATA4的致病变异,通过全外显子组测序鉴定为c.487C>T (p.Pro163Ser)。这种突变导致下游基因的转录活性降低。当我们将这种转录活性水平与其他GATA4变体进行比较时,那些在心脏缺陷和DSD患者中发现的转录活性低于仅心脏缺陷患者的转录活性。这表明心脏的正常发育需要比睾丸发育更严格的GATA4转录调节。此外,当不同的变体与野生型共表达时,转录活性始终低于预期的加性效应,表明变体通过二聚体形成GATA4蛋白的显性负影响。由于这些致病的GATA4变异偶尔在健康父母中被发现,数量性状的阈值模型可能解释它们引起的心脏缺陷或DSD表型。
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来源期刊
Congenital Anomalies
Congenital Anomalies PEDIATRICS-
自引率
0.00%
发文量
49
审稿时长
>12 weeks
期刊介绍: Congenital Anomalies is the official English language journal of the Japanese Teratology Society, and publishes original articles in laboratory as well as clinical research in all areas of abnormal development and related fields, from all over the world. Although contributions by members of the teratology societies affiliated with The International Federation of Teratology Societies are given priority, contributions from non-members are welcomed.
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