Novel pathogenic mutations in disorders of sex development associated genes cause 46,XY complete gonadal dysgenesis

Abstract

Disorders of sex development (DSDs) are congenital conditions in which chromosomal, gonadal and sex is atypical. It is difficult to diagnose and manage patients with DSD in clinical practice, and the molecular etiology of DSD is still not completely understood. Here, we identified two novel pathogenic mutations from three unrelated Chinese patients with 46,XY complete gonadal dysgenesis (CGD) that is a clinical subgroup of DSD by whole exome sequencing. A novel mutation in the SRY gene (c.161delG) was identified in the first patient, and the second patient carried a novel missense mutation in the MAP3K1 gene (c.2117T>G). Bioinformatics analysis found that the deletion of SRY (c.161delG) led to a premature stop codon at amino acid 59 in the SRY protein, which resulted in lacking the DNA binding domain of SRY protein. Functional studies found that the missense mutation in the MAP3K1 gene (c.2117T>G) could interfere with the gene function through increasing the phosphorylation of the downstream targets of MAP3K1, ERK1/2 and p38, which resulted in reducing testis-determining factor SOX9 expression and increasing ovary-promoting factor β-catenin activity. According to the American college of medical genetics and genomics (ACMG) standards and guidelines, these mutations were categorized as “pathogenic” mutations. Thus, our findings provide two novel pathogenic mutations associated with 46,XY CGD that can improve the etiological diagnosis for 46,XY CGD. AbbreviationsUnlabelled TableACMGAmerican college of medical genetics and genomicsATRXalpha thalassemia/mental retardation syndrome X-linkedCADDcombined annotation dependent depletionCBX2chromobox 2CGDcomplete gonadal dysgenesisCTNNB1catenin beta 1DHHdesert hedgehogDSDdisorders of sex developmentEVSexome variant serverFATHMMfunctional analysis through hidden markov modelsFSHfollicle stimulating hormoneHGMDhuman gene mutation databaseHMGhigh mobility groupLHluteinizing hormoneMAP3K1mitogen activated protein kinase kinase kinase 1M-CAPmendelian clinically applicable pathogenicityNR5A1nuclear receptor subfamily 5 group A member 1PCRpolymerase chain reactionPolyPhen-2polymorphism phenotyping v2PROVEANprotein variation effect analyzerqRT-PCRquantitative reverse transcription PCRSIFTsorting intolerant from tolerantSOX9SRY box related 9SRYsex determining region of the Y chromosomeWNT4wingless type MMTV integration site family member 4WT1wilms tumor 1ZNRF3zinc/RING finger protein 3