title: A Novel Missense Mutation 224G>T (R75M) in SRY Coding Region Interferes with Nuclear Import and Results in 46, XY Complete Gonadal Dysgenesis.
abstract: SRY-mutation-caused sex reversal is a rare disease and mostly associated with a de novo mutation since the patients with defective SRY is infertile. There are many reports about SRY-mutation associated 46, XY ovarian disorder of sex development (DSD), but few described their molecular mechanism. Here we report a de novo mutation 224G>T (R75M) in SRY associated with a phenotypic female, 46, XY karyotype and dysgerminoma. The wild and mutated SRY were cloned into recombinant plasmid and expressed in cells in vitro, the result showed the mutated SRY is greatly accumulated in cytoplasm while the wild type SRY is mostly localized in nucleus. To make sure no other genes were involved, we performed the trio-based whole exome sequencing using the DNA samples from the proband and the parents, and no mutations were identified especially in DHH, NR0B1, NR5A1, SOX9 and MAP3K1, indicating the de novo mutation in SRY is the single defect responsible for the female sex reversal. We also used bioinformatics simulation analysis to predict impact of the mutation on SRY function, and find the R75 in wild type SRY can form a hydrogen bond with serine at 91 (S91) that make the SRY protein well fit into the minor groove of target DNA, while the M75 in the mutated SRY can't. Finally, we reviewed SRY mutations based on the available references and analyzed the mutation distribution patterns according to density and continuity, which may be useful for further study of the SRY structure, function, and its relatedness with DSD.
authors.affiliation: Hebei University School of Life Sciences, Baoding, Hebei, China.
authors.forename: Wufang
authors.initials: W
authors.lastname: Fan
authors.affiliation: Hebei University School of Life Sciences, Baoding, Hebei, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Hebei University School of Life Sciences, Baoding, Hebei, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: He
authors.affiliation: Hebei University School of Life Sciences, Baoding, Hebei, China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Hebei University School of Life Sciences, Baoding, Hebei, China.
authors.forename: Chenxing
authors.initials: C
authors.lastname: Yin
authors.affiliation: Hebei University School of Life Sciences, Baoding, Hebei, China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Medical Genetics, Linyi People's Hospital, Shandong, China.
authors.forename: Shuqi
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Institute of Medical Genetics, Linyi People's Hospital, Shandong, China.
authors.forename: Jixia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Medical Genetics, Linyi People's Hospital, Shandong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000328:Adult; D005260:Female; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics*; D051876:Sex-Determining Region Y Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein