A novel MAMLD1 variant in a newborn with hypospadias and elevated 17-hydroxyprogesterone,Hormones

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A novel MAMLD1 variant in a newborn with hypospadias and elevated 17-hydroxyprogesterone
Hormones ( IF 2.4 ) Pub Date : 2023-11-24 , DOI: 10.1007/s42000-023-00513-y
Juanjuan Wang ₁ , Yafeng Sun ₁ , Qian Deng ₁ , Xin Wang ₁ , Wenjuan Cai ₁ , Yuqing Chen ₁

Affiliation

Purpose

Disorders of sex development (DSD) have complex pathogenesis, and evidence suggests an association between MAMLD1 defects and DSD. MAMLD1 is expressed in gonadal tissues and affected males exhibit hypospadias, steroid hormone abnormalities, or gonadal underdevelopment. We performed genetic testing on a newborn patient with severe hypospadias and an elevation of 17-hydroxyprogesterone (17α-OH) for the diagnosis of DSD.

Methods

Genetic testing of the proband and parents was conducted using whole-exome and Sanger sequencing. The identified variant was transfected into HEK293T cells to assess mutant protein expression using western blot (WB) and into steroidogenic NCI-H295R cells to assess MAMLD1 and CYP17A1 transcript levels using qPCR. Molecular dynamics simulations were performed to construct a structural model and analyze potential biological implications.

Results

A novel heterozygous variant was identified in the proband’s MAMLD1, NM_005491.5: c.1619_1637del (p.Gln540Alafs*72), inherited from the mother. In transfected cells, the wild-type and mutant proteins were 86.2 and 68.3 kDa, respectively, indicating the formation of a truncated protein. While MAMLD1 transcription was not affected, CYP17A1 transcription levels decreased with the variant compared to wild-type, suggesting an impact on the transactivation of CYP17A1. The truncated protein exhibited enhanced hydrophobicity, owing to the absence of the C-terminal structural portion, resulting in a looser protein structure.

Conclusion

Severe hypospadias in the proband may be attributed to a novel MAMLD1 variant, whereas the 17α-OH elevation might be related to interference with CYP17A1 transcriptional activation. This study expands the spectrum of MAMLD1 variants and underscores the critical role of genetic testing in the diagnosis of DSD.

中文翻译：

患有尿道下裂和 17-羟基孕酮升高的新生儿中的一种新的 MAMLD1 变异

目的

性发育障碍 (DSD) 具有复杂的发病机制，有证据表明MAMLD1缺陷与 DSD 之间存在关联。 MAMLD1在性腺组织中表达，受影响的男性表现出尿道下裂、类固醇激素异常或性腺发育不良。我们对一名患有严重尿道下裂且 17-羟孕酮 (17α-OH) 升高的新生儿患者进行了基因检测，以诊断 DSD。

方法

使用全外显子组和桑格测序对先证者和父母进行基因检测。将鉴定出的变体转染至 HEK293T 细胞中，以使用蛋白质印迹 (WB) 评估突变蛋白表达，并转染至类固醇生成 NCI-H295R 细胞中，以使用 qPCR 评估MAMLD1和CYP17A1转录水平。进行分子动力学模拟以构建结构模型并分析潜在的生物学意义。

结果

先证者的MAMLD1 NM_005491.5: c.1619_1637del (p.Gln540Alafs*72) 中鉴定出一种新的杂合变异，该变异遗传自母亲。在转染细胞中，野生型和突变型蛋白分别为86.2和68.3 kDa，表明形成了截短的蛋白。虽然MAMLD1转录未受影响，但与野生型相比，该变体的 CYP17A1转录水平降低，表明对CYP17A1反式激活的影响。由于缺少 C 端结构部分，截短的蛋白质表现出增强的疏水性，导致蛋白质结构更松散。