DNA methylation changes in the genome of patients with hypogonadotropic hypogonadism
Erina Suzuki,
Kazuhiko Nakabayashi,
Saki Aoto,
Tsutomu Ogata,
Yoko Kuroki,
Mami Miyado,
Maki Fukami,
Keiko Matsubara
Affiliations
Erina Suzuki
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
Kazuhiko Nakabayashi
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
Saki Aoto
Medical Genome Center, National Center for Child Health and Development, Tokyo, Japan
Tsutomu Ogata
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
Yoko Kuroki
Department of Genome Medicine, National Research Institute for Child Health and Development, Tokyo, Japan; Division of Diversity Research, National Research Institute for Child Health and Development, Tokyo, Japan
Mami Miyado
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
Maki Fukami
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Division of Diversity Research, National Research Institute for Child Health and Development, Tokyo, Japan; Corresponding authors. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, 157-8535, Tokyo, Japan.
Keiko Matsubara
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Division of Diversity Research, National Research Institute for Child Health and Development, Tokyo, Japan; Corresponding authors. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, 157-8535, Tokyo, Japan.
Although some Mendelian neurodevelopmental disorders have been shown to entail specific DNA methylation changes designated as epi-signatures, it remains unknown whether epi-signatures are consistent features of other genetic disorders. Here, we analyzed DNA methylation profiles of patients with hypogonadotropic hypogonadism (HH), a rare neuroendocrine disorder typically caused by monogenic or oligogenic mutations. First, we performed microarray-based genome-wide methylation analyses of nine patients with HH due to ANOS1, SOX2, or SOX10 variants and 12 control individuals. The results showed that 1118 probes were differentially methylated in one or more patients. The differentially methylated probes were highly variable among patients. No significant methylation changes were observed in genes functionally associated with ANOS1, SOX2, or SOX10. Then, we performed pyrosequencing of six selected CpG sites in the nine patients and 35 additional HH patients. The results of the patients were compared with those of 48 fertile men. There were no common methylation changes among these patients, with the exception of hypermethylation of two CpG sites in the ZNF245 promoter of three patients. Hypermethylation of the promoter has previously been reported as a very rare epigenetic polymorphism in the general population. These results indicate that genomes of HH patients have considerable DNA methylation changes; however, these changes are more likely to be physiological epigenetic variations than disease-specific epi-signatures. Our data suggest a possible association between hypermethylation of the ZNF254 promoter and HH, which needs to be examined in future studies.
