New NR5A1 mutations and phenotypic variations of gonadal dysgenesis

Mutations in NR5A1 have been reported as a frequent cause of 46,XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46,XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs*83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling’s family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations.

NR5A1基因（NR5A1）突变已被报道为46,XY性别发育障碍（46,XY disorders of sex development, DSD）的常见致病原因，该类障碍伴随广泛的表型谱，涵盖不育症、生殖器模糊畸形、无睾症、性腺发育不全及女性外生殖器表型。本研究对4例携带NR5A1基因3种新型杂合突变的46,XY DSD患者开展临床随访，上述突变分别为位于DNA结合域内的p.T40P错义突变、p.18DKVSG22del非移码缺失，以及家族性p.Y211Tfs*83移码突变。针对该错义突变与非移码缺失突变的功能分析显示，二者均具有有害性特征，表现为DNA结合能力与反式激活能力丧失。DNA结合域内的突变与家族性移码突变，均与高度可变的内分泌指标及表型表现相关。患者表型差异显著，从可自发青春期启动、具备足量睾酮合成能力且可能拥有生育潜能的男性，到伴或不伴苗勒管结构、存在原发性闭经的女性均有覆盖。对该患者同胞家庭的外显子测序结果显示，TBX2基因可能是NR5A1突变患者性腺发育的潜在修饰因子。