title: 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.
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.
authors: Division of Pediatrics, Dokkyo University Koshigaya Hospital, 2-1-50 Minami Koshigaya, Koshigaya, Saitama 343-8555, Japan. saka343@dokkyomed.ac.jp
authors: Satoru
authors: S
authors: Sakazume
authors: Hirofumi
authors: H
authors: Ohashi
authors: Yuki
authors: Y
authors: Sasaki
authors: Naoki
authors: N
authors: Harada
authors: Katsumi
authors: K
authors: Nakanishi
authors: Hidenori
authors: H
authors: Sato
authors: Mitsuru
authors: M
authors: Emi
authors: Kazushi
authors: K
authors: Endoh
authors: Ryoichi
authors: R
authors: Sohma
authors: Yasuhiro
authors: Y
authors: Kido
authors: Toshiro
authors: T
authors: Nagai
authors: Takeo
authors: T
authors: Kubota
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D019175:DNA Methylation; D020869:Gene Expression Profiling; D018392:Genomic Imprinting; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D059785:Karyotype; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011218:Prader-Willi Syndrome / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic / Q000235:genetics*; D049951:X Chromosome Inactivation; D055517:snRNP Core Proteins / Q000235:genetics
chemical_list: D015415:Biomarkers; D026901:Membrane Transport Proteins; C489600:OCA2 protein, human; D012333:RNA, Messenger; C526417:SNRPN protein, human; D055517:snRNP Core Proteins