Kalfa Nicolas, Liu Benchun, Klein Ophir, Audran Francoise, Wang Ming-Hsieh, Mei Cao, Sultan Charles, Baskin Laurence S
Department of Pediatric Urology, Center for the Study and Treatment of Hypospadias, Children's Medical Center, University of California San Francisco, 400 Parnassus Avenue, A 640, San Francisco, California 94143, USA.
Eur J Endocrinol. 2008 Oct;159(4):453-8. doi: 10.1530/EJE-08-0085. Epub 2008 Jul 17.
Mutations in chromosome X open reading frame 6 (CXorf6), a recently described candidate gene involved in the development of male genitalia, have been found in patients with complex 46,XY disorders of sexual development (46,XY DSD) including micropenis, bifid scrotum, and penoscrotal hypospadias. The objective of this work was to identify genomic variants of CXorf6 in patients with isolated hypospadias, severe or non-severe.
Forty-one patients with glandular to perineal hypospadias and thirty controls were studied. Direct sequencing for coding exons 3-6 of CXorf6 and their flanking splice sites was performed on DNA extracted from foreskin collected from surgery. Secondary and tertiary structures of the protein were predicted using NNpredict and Protein Homology/analogY Recognition Engine engines.
Four mutations (9.7% of cases) were identified. One missense mutation (1295T>C, V432A) and two deletions (325delG, predicted to cause a stop codon L121X) occurred in patients with penoscrotal and proximal hypospadias. One patient with subcoronal hypospadias had CAG-repeat amplification in the second polyglutamine domain of CXorf6. Secondary structure prediction indicated that this insertion occurred in a helix element of the protein. The tertiary structure prediction showed an alteration of the shape of the protein and crowding between domains.
CXorf6 mutations are associated with isolated hypospadias of varying severity. However, the pathophysiology of these mutations and the function of the CXorf6 gene product remain to be investigated.
在患有复杂46，XY性发育障碍（46，XY DSD）的患者中发现了X染色体开放阅读框6（CXorf6）的突变，这些患者包括小阴茎、阴囊分裂和阴茎阴囊型尿道下裂。该基因是最近描述的一个参与男性生殖器发育的候选基因。本研究的目的是确定单纯性尿道下裂患者（严重或非严重）中CXorf6的基因组变异。
对41例患有阴茎头型至会阴型尿道下裂的患者和30名对照进行研究。对从手术切除的包皮中提取的DNA进行CXorf6编码外显子3 - 6及其侧翼剪接位点的直接测序。使用NNpredict和蛋白质同源性/相似性识别引擎预测蛋白质的二级和三级结构。
共鉴定出4个突变（占病例的9.7%）。1个错义突变（1295T>C，V432A）和2个缺失突变（325delG，预计导致终止密码子L121X）出现在阴茎阴囊型和近端尿道下裂患者中。1例冠状沟下型尿道下裂患者在CXorf6的第二个聚谷氨酰胺结构域出现CAG重复扩增。二级结构预测表明该插入发生在蛋白质的螺旋元件中。三级结构预测显示蛋白质形状改变且结构域之间拥挤。
CXorf6突变与不同严重程度的单纯性尿道下裂有关。然而，这些突变的病理生理学以及CXorf6基因产物的功能仍有待研究。
