BMC Genomics. 2008 Jan 28;9(1):50 [Epub ahead of print]
Genomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region.
Jiang YH, Wauki K, Liu Q, Bressler J, Pan Y, Kashork C, Shaffer LG, Beaudet AL.
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BACKGROUND: Prader-Willi syndrome (PWS) is a neurobehavioral disorder characterized by neonatal hypotonia, childhood obesity, dysmorphic features, hypogonadism, mental retardation, and behavioral problems. Although PWS is most often caused by a paternal interstitial deletion of a 6-Mb region of chromosome 15q11-q13, the identity of the exact protein coding or noncoding RNAs whose deficiency produces the PWS phenotype is uncertain. There are also reports describing a PWS-like phenotype in a subset of patients with full mutations in the FMR1 (fragile X mental retardation 1) gene. Taking advantage of the human genome sequence, we have performed extensive sequence analysis and molecular studies for the PWS candidate region. RESULTS: We have characterized transcripts for the first time for two UCSC Genome Browser predicted protein-coding genes, GOLGA8E (golgin subfamily a, 8E) and WHDC1L1 (WAS protein homology region containing 1-like 1) and have further characterized two previously reported genes, CYF1P1 and NIPA2; all four genes are in the region close to the proximal/centromeric deletion breakpoint (BP1). CYFIP1 was reported as a cytoplasmic fragile X mental retardation protein (FMRP) interacting protein. GOLGA8E belongs to the golgin subfamily of coiled-coil proteins associated with the Golgi apparatus. Six out of 16 golgin subfamily proteins in the human genome have been mapped in the chromosome 15q11-q13 and 15q24-q26 regions. We have also identified more than 38 copies of GOLGA8E-like sequence in the 15q11-q14 and 15q23-q26 regions which supports the presence of a GOLGA8E-associated low copy repeat (LCR). Analysis of the 15q11-q13 region by PFGE also revealed a polymorphic region between BP1 and BP2. WHDC1L1 is a novel gene with similarity to mouse Whdc1 (WAS protein homology region 2 domain containing 1) and human JMY protein (junction-mediating and regulatory protein). Expression analysis of cultured human cells and brain tissues from PWS patients supports a conclusion of biallelic expression CYFIP1 and NIPA2. However, we were not able to determine the allelic specific expression pattern for GOLGA8E and WHDC1L1 because these two genes have highly related sequences that might also be expressed. CONCLUSIONS: We have presented an updated version of a sequence-based physical map for a complex chromosomal region, and we raise the possibility of polymorphism in the genomic orientation of the BP1 to BP2 region. The identification of two new proteins encoded by genes in the 15q11-q13 may extend our understanding of the molecular basis of PWS. The finding that a FMRP interacting protein maps within the PWS candidate region provides a framework for further investigation of the occurrence of a PWS-like phenotype in some fragile X patients. In terms of copy number variation and gene organization, this is one of the most polymorphic regions of the human genome, and perhaps the single most polymorphic region of this type.

[Note: The Golgi apparatus is a stack of 6-8 plate-like membranous compartments and associated vesicles and vacuoles, often located near the centrosome. It has four functionally distinct compartments: cis, medial and trans Golgi stacks, and the trans Golgi network (TGN). The first three are involved in posttranslational modifications of proteins (e.g., N- or O-glycosylation, sulfation, processing of acid hydrolases), while the TGN is involved in sorting the proteins to their final destination (e.g., to lysosomes, to secretory vesicles, or to plasma membrane).]

Categories: 2008, PWS, PWS genes, Glycosylation, FMR1, CYFIP1, NIPA2, GOLGA8E, WHDC1L1, Fragile X PWS phenotype