Novel NR5A1 Pathogenic Variants Cause Phenotypic Heterogeneity in 46,XY Disorders of Sex Development

被引:5
作者
Sudhakar, Digumarthi V. S. [1 ]
Jaishankar, Shveta [2 ]
Regur, Phanindranath [1 ]
Kumar, Umesh [1 ]
Singh, Raghvendra [1 ]
Kabilan, Usha [1 ]
Namduri, Sree [1 ]
Dhyani, Jaishree [1 ]
Gupta, Nalini J. [3 ]
Chakravarthy, Baidyanath [3 ]
Vaman, Khadilkar [4 ]
Shabir, Iram [5 ]
Khadgawat, Rajesh [5 ]
Deenadayal, Mamata [6 ]
Chaitanya, Datar A. [7 ]
Dada, Rima [5 ]
Sharma, Yogendra [1 ,8 ]
Anand, Anuranjan [2 ]
Thangaraj, Kumarasamy [1 ]
机构
[1] CSIR Ctr Cellular & Mol Biol, Hyderabad 500007, Telangana, India
[2] Jawaharlal Nehru Ctr Adv Sci Res JNCASR, Bengaluru, India
[3] Inst Reprod Med, Kolkata, India
[4] Jehangir Hosp & Res Ctr, Pune, Maharashtra, India
[5] All India Inst Med Sci, New Delhi, India
[6] Infertil Inst & Res Ctr, Secunderabad, India
[7] Bharati Hosp & Res Ctr, Pune, Maharashtra, India
[8] Indian Inst Sci Educ & Res IISER, Berhampur, Odisha, India
关键词
SF1; 46; XY disorders of sex development; FACTOR-I SF-1; STEROIDOGENIC FACTOR-1; XY DISORDERS; NR5A1; MUTATIONS; BINDING; TESTIS; SF1; RECOGNITION; PROMOTER;
D O I
10.1159/000505527
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Steroidogenic factor 1 (NR5A1/SF1) is a key transcription factor that is known to regulate the development of adrenal glands and gonads and is also involved in steroidogenesis. Several pathogenic NR5A1 variants have been reported to cause 46,XY disorders of sex development (DSD), with varying clinical phenotypes ranging from hypospadias to complete gonadal dysgenesis. Most often, the primary cause of DSD is due to variants in gene(s) related to gonadal development or the steroidogenic pathway. In the present study, we have analyzed 64 cases of 46,XY DSD for pathogenic NR5A1 variants. We report a total of 3 pathogenic variants of which 2 were novel (p.Gly22Ser and p.Ser143Asn) and 1 was already known (p.Ser32Asn). Functional studies have revealed that the 2 mutations p.Gly22Ser and p.Ser32Asn could significantly affect DNA binding and transactivation abilities. Further, these mutant proteins showed nuclear localization with aggregate formation. The third mutation, p.Ser143Asn, showed unspeckled nuclear localization and normal DNA binding, but the ability of transcriptional activation was significantly reduced. In conclusion, we recommend screening for NR5A1 pathogenic variants in individuals with features of 46,XY DSD for better diagnosis and management.
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收藏
页码:178 / 186
页数:9
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