Human Genetics

, Volume 131, Issue 1, pp 121–130

Spread of X-chromosome inactivation into chromosome 15 is associated with Prader–Willi syndrome phenotype in a boy with a t(X;15)(p21.1;q11.2) translocation

  • Satoru Sakazume
  • Hirofumi Ohashi
  • Yuki Sasaki
  • Naoki Harada
  • Katsumi Nakanishi
  • Hidenori Sato
  • Mitsuru Emi
  • Kazushi Endoh
  • Ryoichi Sohma
  • Yasuhiro Kido
  • Toshiro Nagai
  • Takeo Kubota
Original Investigation

DOI: 10.1007/s00439-011-1051-4

Cite this article as:
Sakazume, S., Ohashi, H., Sasaki, Y. et al. Hum Genet (2012) 131: 121. doi:10.1007/s00439-011-1051-4
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Abstract

X-chromosome inactivation (XCI) is an essential mechanism in females that compensates for the genome imbalance between females and males. It is known that XCI can spread into an autosome of patients with X;autosome translocations. The subject was a 5-year-old boy with Prader–Willi syndrome (PWS)-like features including hypotonia, hypo-genitalism, hypo-pigmentation, and developmental delay. G-banding, fluorescent in situ hybridization, BrdU-incorporated replication, human androgen receptor gene locus assay, SNP microarrays, ChIP-on-chip assay, bisulfite sequencing, and real-time RT-PCR were performed. Cytogenetic analyses revealed that the karyotype was 46,XY,der(X)t(X;15)(p21.1;q11.2),−15. In the derivative chromosome, the X and half of the chromosome 15 segments showed late replication. The X segment was maternal, and the chromosome 15 region was paternal, indicating its post-zygotic origin. The two chromosome 15s had a biparental origin. The DNA methylation level was relatively high in the region proximal from the breakpoint, and the level decreased toward the middle of the chromosome 15 region; however, scattered areas of hypermethylation were found in the distal region. The promoter regions of the imprinted SNRPN and the non-imprinted OCA2 genes were completely and half methylated, respectively. However, no methylation was found in the adjacent imprinted gene UBE3A, which contained a lower density of LINE1 repeats. Our findings suggest that XCI spread into the paternal chromosome 15 led to the aberrant hypermethylation of SNRPN and OCA2 and their decreased expression, which contributes to the PWS-like features and hypo-pigmentation of the patient. To our knowledge, this is the first chromosome-wide methylation study in which the DNA methylation level is demonstrated in an autosome subject to XCI.

Supplementary material

439_2011_1051_MOESM1_ESM.doc (94 kb)
Supplemental Table 1 (DOC 93 kb)
439_2011_1051_MOESM2_ESM.doc (654 kb)
Supplemental Table 2 (DOC 81 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Satoru Sakazume
    • 1
  • Hirofumi Ohashi
    • 2
  • Yuki Sasaki
    • 3
  • Naoki Harada
    • 3
  • Katsumi Nakanishi
    • 4
  • Hidenori Sato
    • 4
    • 5
  • Mitsuru Emi
    • 4
    • 5
  • Kazushi Endoh
    • 6
  • Ryoichi Sohma
    • 1
  • Yasuhiro Kido
    • 1
  • Toshiro Nagai
    • 1
  • Takeo Kubota
    • 6
  1. 1.Division of PediatricsDokkyo University Koshigaya HospitalKoshigayaJapan
  2. 2.Division of GeneticsSaitama Children’s Medical CenterHasudaJapan
  3. 3.Department of Molecular Genetic Research and AnalysisAdvanced Medical Science Research Center, Mitsubishi Chemical Medience CorporationTokyoJapan
  4. 4.DNA Chip Research IncYokohamaJapan
  5. 5.Department of Neurology, Hematology, Metabolism, Endocrinology and DiabetologyYamagata University School of MedicineYamagataJapan
  6. 6.Department of Epigenetic Medicine, Faculty of Medicine, Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiChuoJapan

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