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A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9.

ABSTRACT: The 46,XX testicular DSD (disorder/difference of sexual development) and 46,XX ovotesticular DSD (46,XX TDSD and 46,XX OTDSD) phenotypes are caused by genetic rearrangements or point mutations resulting in imbalance between components of the two antagonistic, pro-testicular and pro-ovarian pathways; however, the genetic causes of 46,XX TDSD/OTDSD are not fully understood, and molecular diagnosis for many patients with the conditions is unavailable. Only recently few mutations in the WT1 (WT1 transcription factor; 11p13) gene were described in a group of 46,XX TDSD and 46,XX OTDSD individuals. The WT1 protein contains a DNA/RNA binding domain consisting of four zinc fingers (ZnF) and a three-amino acid (KTS) motif that is present or absent, as a result of alternative splicing, between ZnF3 and ZnF4 (±KTS isoforms). Here, we present a patient with 46,XX TDSD/OTDSD in whom whole exome sequencing revealed a heterozygous de novo WT1 c.1437A>G mutation within an alternative donor splice site which is used for -KTS WT1 isoform formation. So far, no mutation in this splice site has been identified in any patient group. We demonstrated that the mutation results in the retention of intron 9 in the mature mRNA of the 46,XX TDSD/OTDSD patient. In cases when the erroneous mRNA is translated, exclusively the expression of a truncated WT1 +KTS protein lacking ZnF4 and no -KTS protein occurs from the mutated allele of the patient. We discuss potential mechanisms and pathways which can be disturbed upon two conditions: Absence of Zn4F and altered +KTS/-KTS ratio.

SUBMITTER: Sirokha D

PROVIDER: S-EPMC8698877 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectives: XX male syndrome is part of the disorders of sex development (DSD). The patients generally have normal external genitalia and discover their pathology in adulthood because of infertility. There are no guidelines regarding XX male syndrome, so the aim of our study was to evaluate the literature evidence in order to guide the physicians in the management of these type of patients. Materials and Methods: We performed a systematic review of the available literature in September 2018, using MEDLINE, Web of Science, Embase and Google Scholar database to search for all published studies regarding XX male syndrome according to PRISMA guidelines. The following search terms were used: "46 XX male", "DSD", "infertility", "hypogonadism". Results: After appropriate screening we selected 37 papers. Mean (SD) age was 33.14 (11.4) years. Hair distribution was normal in 29/39 patients (74.3%), gynecomastia was absent in 22/39 cases (56.4%), normal testes volume was reported in 0/14, penis size was normal in 26/32 cases (81.2%), pubic hair had a normal development in 6/7 patients (85.7%), normal erectile function was present in 27/30 cases (90%) and libido was preserved in 20/20 patients (100%). The data revealed the common presence of hypergonadotropic hypogonadism. All patients had a 46,XX karyotype. The sex-determining region Y (SRY) gene was detected in 51/57 cases. The position of the SRY was on the Xp in the 97% of the cases. Conclusions: An appropriate physical examination should include the evaluation of genitalia to detect cryptorchidism, hypospadias, penis size, and gynecomastia; it is important to use a validated questionnaire to evaluate erectile dysfunction, such as the International Index of Erectile Function (IIEF). Semen analysis is mandatory and so is the karyotype test. Abdominal ultrasound is useful in order to exclude residual Müllerian structures. Genetic and endocrine consultations are necessary to assess a possible hypergonadotropic hypogonadism. Testicular sperm extraction is not recommended, and adoption or in vitro fertilization with a sperm donor are fertility options.

Project description:Patients with Disorders of Sex Development (DSD), especially those with gonadal dysgenesis and hypovirilization are at risk of developing malignant type II germ cell tumors/cancer (GCC) (seminoma/dysgerminoma and nonseminoma), with either carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesion. In 10-15% of 46,XY gonadal dysgenesis cases (i.e., Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of DNA. Frasier syndrome (FS) is characterized by gonadal dysgenesis with a high risk for development of GB as well as chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the Wilms' tumor 1 gene (WT1). Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development. Embryonic germ cells residing in this unfavourable micro-environment have an increased risk for malignant transformation. Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY. Functional in vitro studies showed no convincing protein malfunctioning. Laparoscopic examination revealed streak ovaries and a normal, but small, uterus. Pathological examination demonstrated bilateral GB and dysgerminoma, confirmed by immunohistochemistry. Occurrence of a delayed progressive kidney failure (focal segmental glomerular sclerosis) triggered analysis of WT1, revealing a pathogenic splice-site mutation in intron 9. Analysis of the SRY gene in an additional five FS cases did not reveal any mutations. The case presented shows the importance of multi-gene based diagnosis of DSD patients, allowing early diagnosis and treatment, thus preventing putative development of an invasive cancer.

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A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9.

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