ESPE Abstracts (2014) 82 P-D-2-1-573

Mutation Analysis of kdm3a (Lysine-Specific Demethylase 3a) in Patients with Hypospadias

Masafumi Kona,d, Maki Igarashia, Yoko Izumia, Yuko Kato-Fukuia, Kentaro Mizunob, Yutaro Hayashib, Kenjiro Kohrib, Yoshiyuki Kojimac, Katsuya Nonomurad, Tsutomu Ogataa,e & Maki Fukamia


aDepartment of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; bDepartment of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; cDepartment of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan; dDepartment of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan; eDepartment of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan


Background: Hypospadias is a relatively common form of 46,XY disorders of sex development. Although several genes have been implicated in the development of hypospadias, molecular basis of the majority of cases remain unknown. Recently, targeted disruption of lysine-specific demethylase 3A (KDM3A) were shown to cause defective sex development in male mice.

Objective and hypotheses: The aim of this study was to clarify whether KDM3A mutations underlie hypospadias in human.

Method: We performed mutation screening of KDM3A in 66 patients with hypospadias. The functional consequences of nucleotide changes were assessed by in silico assays.

Results: We identified a heterozygous nucleotide change in KDM3A (p.D201H, c.601G>C) in a patient. The nucleotide change was assessed as ‘probably damaging’ by PolyPhen2 and ‘damaging’ by SIFT. The p.D201H variant was Hitherto unreported. The patient manifested penoscrotal hypospadias and right vesicourethral reflux without micropenis or undescended testis. Endocrine evaluation at one year of age showed normal levels of testosterone, LH, and FSH.

Conclusion: The results indicate that sequence alterations in KDM3A may constitute a rare etiology of hypospadias in human