Genomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region.
Genomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region.
复制标题
DOI：
10.1186/1471-2164-9-50
复制
发表时间：
2008-01-28
期刊：
影响因子：
4.4
通讯作者：
Beaudet AL
中科院分区：
文献类型：
--
作者：
Jiang YH;Wauki K;Liu Q;Bressler J;Pan Y;Kashork CD;Shaffer LG;Beaudet AL
Prader-Willi综合征（PWS）是一种以新生儿肌张力减退、儿童肥胖、畸形、性腺功能减退、智力低下和行为问题为特征的神经行为障碍。虽然PWS最常由染色体15 q11-q13的6-Mb区域的父本间质性缺失引起，但其缺陷产生PWS表型的确切蛋白质编码或非编码RNA的身份尚不确定。也有报道描述了在FMR 1（脆性X智力低下1）基因中具有完全突变的患者亚组中的PWS样表型。利用人类基因组序列，我们已经进行了广泛的序列分析和分子研究的PWS候选区域。我们首次对两个UCSC基因组浏览器预测的蛋白编码基因GOLGA 8 E（golgin亚家族a，8 E）和WHDC 1 L1（WAS蛋白同源区含有1-like 1）的转录本进行了表征，并进一步表征了两个先前报道的基因CYF 1 P1和NIPA 2;所有四个基因都位于靠近近端/着丝粒缺失断点（BP 1）的区域。GOLGA 8 E属于与高尔基体相关的卷曲螺旋蛋白的高尔基体蛋白亚家族。人类基因组中16个Golgin亚家族蛋白中的6个已定位于染色体15 q11-q13和15 q24-q26区域。我们还在15 q11-q14和15 q23-q26区域鉴定了超过38个GOLGA 8 E样序列拷贝，这支持了GOLGA 8 E相关低拷贝重复序列（LCR）的存在。PFGE对15 q11-q13区域的分析也揭示了BP 1和BP 2之间的多态性区域。WHDC 1 L1是一个与小鼠WHDC 1（WAS蛋白同源区2结构域含1）和人JMY蛋白（连接介导和调节蛋白）相似的新基因。来自PWS患者的培养的人细胞和脑组织的表达分析表明CYFIP 1和NIPA 2是双等位基因表达的。然而，我们不能确定GOLGA 8 E和WHDC 1 L1的等位基因特异性表达模式，因为这两个基因具有高度相关的序列，也可能表达。我们已经提出了一个更新版本的基于序列的物理地图的一个复杂的染色体区域，我们提出了多态性的可能性在基因组方向的BP 1到BP 2区域。15 q11-q13区域基因编码的两个新蛋白GOLGA 8 E和WHDC 1 L1的鉴定可能扩展我们对PWS分子基础的理解。就拷贝数变异和基因组织而言，这是人类基因组中最具多态性的区域之一，也许是这种类型中最具多态性的区域。
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. 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). 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 indicates that CYFIP1 and NIPA2 are biallelically expressed. However, we were not able to determine the allele-specific expression pattern for GOLGA8E and WHDC1L1 because these two genes have highly related sequences that might also be expressed. 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 GOLGA8E and WHDC1L1 encoded by genes in the 15q11-q13 region may extend our understanding of the molecular basis of PWS. 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.
登录
查看更多内容
影响因子：
9.8
作者：
Conroy, JM;Grebe, TA;Schwartz, S
通讯作者：
Schwartz, S
影响因子：
4.4
作者：
Buiting, Karin;Nazlican, Huelya;Horsthemke, Bernhard
通讯作者：
Horsthemke, Bernhard
影响因子：
2
作者：
Descheemaeker, MJ;Govers, V;Fryns, JP
通讯作者：
Fryns, JP
影响因子：
30.8
作者：
Gérard, M;Hernandez, L;Stewart, CL
通讯作者：
Stewart, CL
影响因子：
3.5
作者：
Boccaccio, I;Glatt-Deeley, H;Muscatelli, F
通讯作者：
Muscatelli, F