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

• Published in: Human genetics 2012, Vol.131 (1), p.121-130
• Main Authors: Sakazume, Satoru, Ohashi, Hirofumi, Sasaki, Yuki, Harada, Naoki, Nakanishi, Katsumi, Sato, Hidenori, Emi, Mitsuru, Endoh, Kazushi, Sohma, Ryoichi, Kido, Yasuhiro, Nagai, Toshiro, Kubota, Takeo
• Format: Article
• Language: English
• Subjects: Analysis; Androgen receptors; Androgens; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; Bisulfite; Breakpoints; Child, Preschool; chromosome 15; Chromosome Aberrations; Chromosome Banding; Chromosome translocations; Chromosomes; Chromosomes, Human, Pair 15 - genetics; Chromosomes, Human, X - genetics; Cloning; Cytogenetics; DNA Methylation; DNA microarrays; Fluorescence in situ hybridization; Gene Expression Profiling; Gene Function; Genes; Genetic aspects; Genomes; Genomic Imprinting; Genomics; Human Genetics; Humans; Hybridization; In Situ Hybridization, Fluorescence; Karyotype; Karyotypes; Male; Medicine; Membrane Transport Proteins - genetics; Metabolic Diseases; Methylation; Molecular Medicine; Oligonucleotide Array Sequence Analysis; Original Investigation; Phenotype; Polymerase chain reaction; Polymorphism, Single Nucleotide - genetics; Prader-Willi syndrome; Prader-Willi Syndrome - genetics; Promoters; Real-Time Polymerase Chain Reaction; Replication; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Single-nucleotide polymorphism; snRNP Core Proteins - genetics; Sulfites; Translocation, Genetic - genetics; Ubiquitin-protein ligase; X Chromosome Inactivation; X chromosomes
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-011-1051-4

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.