Inherited missense mutation occurred Arginine76 of SRY gene not account for familial 46, XY sex reversal.

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SRY is one of the important genes involved in the process of human sex determination. The disturbed sex determination caused by SRY mutation accounts for 10-15% of cases with 46, XY sex reversal. Recently, three distal enhancers have been identified upstream of the SOX9 gene.The purpose of this study was to investigate the molecular etiology of 46,XY sex reversal in 3 familial patients and a sporadic patient.Next-generation sequencing (NGS) was used to reveal the genotype and inherited pattern. Copy number variations (CNVs) and single nucleotide polymorphism (SNP) haplotyping were analyzed to observe the alteration of enhancers of SOX9. Transcriptional activity of SRY mutation were assessed by a dual luciferase reporting system, and nucleartranslocation was observed by confocalmicroscopy.Two novel SRY gene mutations, p.Arg76Leu and p.Glu89flx15, were identified. In the pedigree with multiple patients, p.Arg76Leu mutation in SRY and p.Gly212Ser mutation in NR5A1 were identified in the proband. The heterozygous deletion far upstream of the SOX9 gene in chromosome 7 was identified in the 3 patients in this family, containing the distal enhancer eSR-A of SOX9 but not eSR-B and eALDI. The frameshift mutation p.Glu89flx15 was revealed to inhibit the transcriptional activity of the target gene, whereas the missense mutation p.Arg76Leu barely showed an effect.In contrast to sporadic cases, inherited single nucleotide variations (SNVs) of SRY are not the main cause of the severe phenotype of 46,XY sex reversal, and the enhancers of SOX9 should be investigated carefully in such patients.



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