Analysis Of A Case Of Primary Amenorrhea With Hypertension Carrying Mutations In NUP107 And Review Of The Literature

Background:Primary amenorrhea can be divided into defect of outflow tract,defect of gonadal gland,defect of hypothalamic-pituitary system,other endocrine disorder and constitutional delay.Defect of gonadal gland can be further divided into gonadal dysgenesis,polycystic ovary syndrome and premature ovarian failure.Premature ovarian failure can be caused by multiple reasons,patients with which may present with absent menarche,premature exhaustion of ovarian follicles or cease of folliculogenesis before age of 40.Hypertension is the leading independent threat of death and disability globally,as well as the most popular preventable risk factor for cardiopathies,chronic nephropathies and cognitive disorders.It is reported that approximately 90-95%of hypertension is primary amenorrhea,which can not only be caused by chromosomal gene variation,but also be related to mitochondrial genome.With the development of gene diagnosis technology,more and more relevant rare diseases have been diagnosed and treated properly.NUP107 was first found in 1994.It is recognized as a key module of nuclear pore complex and participate in the bidirectional nucleocytoplasmic trafficking as well as the mitotic apparatus of cytoplasmic division.In recent years,multiple reports have demonstrated that NUP107 are closely associated with ovarian function.However,no report has suggested that NUP107 gene variants can lead to primary amenorrhea with hypertension.Objectives:This study aims to explore the relationship between primary amenorrhea,hypertension and NUP107 gene based on literature review and case analysis,so as to promote the early diagnosis and treatment of diseases.It lays a foundation for further study on the relationship between NUP107 and diseases,as well as gene diagnose methods of rare diseases.Methods:The complete clinical data of a patient with premature ovarian failure and primary hypertension admitted to the Department of endocrinology of the Provincial Hospital Affiliated to Shandong University in July 2020 were collected and reported.With the informed consent of patient and 5 family members,2-3ml peripheral blood samples were obtained from these 6 individuals.Genomic DNA was then extracted from the blood samples.Whole exome sequencing was performed on the genomic DNA samples of patients,including the exon region and adjacent intron region(50bp)of all human genes 20099.The pathogenicity of the screened variants was evaluated according to the Standards and Guidelines for interpretation of Sequence Variation,and classified using the nomenclature of the Human Genome Variation Society.When pathogenic or suspected pathogenic variations are detected in autosomal recessive genes,next generation sequencing and/or Sanger sequencing are performed to ensure 100%coverage of the coding sequence of the gene.According to the mutation sites of the proband,Sanger sequencing was carried out among the rest 5 individuals on the exon and peripheral intron regions of the sites.At last,in order to further explore the relationship between NUP107 and diseases,bioinformatics analysis was carried out on the transcriptome sequencing results of untreated DLD-1 cells and DLD-1 cells with nup107 gene knockout.Result:After discharge from the hospital,the patient insisted on using antihypertensive drugs and artificial cycle therapy.The patient is still lack of spontaneous menstruation.The systolic blood pressure range around 160mmHg,but no symptom has been mentioned by the patient during follow-up visits.Two heterozygous variation sites were detected in NUP107 gene of the patient,which were both autosomal recessive inherited.The mutations were nonsense mutation c.709G>T(p.E237X)and missense mutation c.1063C>T(p.R355C).The father and paternal grandfather of the patient carry heterozygous variation c.709G>T.The mother of the patient carries heterozygous variation c.1063C>T.However,the paternal grandmother and brother of the patient carry none of the variations above.Mutation c.709G>T is novel,which can lead to abnormal translation and premature termination of the encoding protein.It may affect the function of the protein product and is defined as suspected pathogenic variation.Mutation c.1063C>T has been reported to be related to premature ovarian failure,and the occurrence frequency of which is T=0.000021.It was predicted by Bioinformation Analysis software to be likely pathogenic and was considered to have clinical uncertain significance.During comparation of GSM3937080-82 group(transcriptome sequencing data of DLD-1 cells with nup107 gene knockout)and GSM5213038-40 group(transcriptome sequencing data of untreated DLD-1 cells),a total of 1026 differential genes were screened.The 20 main enriched pathways included pathways of blood vessel development,growth factor activity and positive regulation of reproductive process.Conclusion:1.A 21-year-old case with primary amenorrhea and hypertension carrying compound heterozygous mutations in Nup107 was reported.The patient was diagnosed as premature ovarian failure and unexplained early-onset resistant hypertension.2.Bioinformatics analysis suggested that NUP107 may be closely related to pathways of blood vessel development,growth factor activity and positive regulation of reproductive process.It is speculated that NUP107 gene variations may be related to the occurrence of hypertension and primary amenorrhea.3.Compound heterozygous mutations of NUP107 gene,which are(c.709G>T,p.E237X)and(c.1063C>T,pR355C),may be the cause of premature ovarian failure of the patient.