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斯-韦二氏综合征:COL11A1基因的进一步突变及其他位点异质性的证据

Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity.

作者信息

Martin S, Richards A J, Yates J R, Scott J D, Pope M, Snead M P

机构信息

Department of Pathology, University of Cambridge, UK.

出版信息

Eur J Hum Genet. 1999 Oct-Nov;7(7):807-14. doi: 10.1038/sj.ejhg.5200377.

Abstract

Stickler syndrome (hereditary arthro-ophthalmopathy) is a dominantly inherited connective tissue disorder with ocular, oro-facial, auditory and skeletal manifestations. It is genetically and phenotypically heterogeneous with the majority of families having mutations in the gene encoding type II collagen (COL2A1) and exhibiting a characteristic 'membranous' or type 1 vitreous phenotype. More recently a novel mutation in the gene encoding the alpha1 chain of type XI collagen (COL11A1) was reported in a Stickler syndrome pedigree with a different 'beaded' or type 2 vitreous phenotype. In the present study five more families with the type 2 vitreous phenotype were examined for linkage to four candidate genes: COL2A1, COL5A2, COL11A1 and COL11A2. Two families were linked to COL11A1 and sequencing identified mutations resulting in shortened alphal(XI) collagen chains, one via exon skipping and the other via a multiexon deletion. One of the families showed weak linkage to COL5A2 but sequencing the open reading frame failed to identify a mutation. In the remaining two families all four loci were excluded by linkage analysis. These data confirm that mutations in COL11A1 cause Stickler syndrome with the type2 vitreous phenotype and also reveal further locus heterogeneity.

摘要

斯-韦二氏综合征(遗传性关节眼病)是一种显性遗传的结缔组织疾病,具有眼部、口腔面部、听觉和骨骼表现。它在遗传和表型上具有异质性,大多数家族在编码II型胶原(COL2A1)的基因中存在突变,并表现出特征性的“膜状”或1型玻璃体表型。最近,在一个具有不同“串珠状”或2型玻璃体表型的斯-韦二氏综合征家系中,报道了编码XI型胶原α1链(COL11A1)的基因发生了新的突变。在本研究中,对另外5个具有2型玻璃体表型的家系进行了检测,以确定与4个候选基因(COL2A1、COL5A2、COL11A1和COL11A2)的连锁关系。2个家系与COL11A1连锁,测序鉴定出导致α1(XI)胶原链缩短的突变,一个是通过外显子跳跃,另一个是通过多个外显子缺失。其中一个家系与COL5A2表现出弱连锁,但对开放阅读框进行测序未能鉴定出突变。在其余2个家系中,通过连锁分析排除了所有4个基因座。这些数据证实,COL11A1中的突变会导致具有2型玻璃体表型的斯-韦二氏综合征,同时也揭示了进一步的基因座异质性。

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