The phenotypic spectrum of COL2A1 mutations
The phenotypic spectrum of COL2A1 mutations
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DOI：
10.1002/humu.20179
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发表时间：
2005-07-01
期刊：
影响因子：
3.9
通讯作者：
Ikegawa, S
中科院分区：
文献类型：
--
作者：
Nishimura, G;Haga, N;Ikegawa, S
COL2A1的杂合突变产生几种临床实体，统称为11型胶原病。这些疾病不仅损害骨骼生长，而且引起眼和耳鼻喉的异常。典型表型包括不同严重程度的脊椎骨骺发育不良（SED）谱、Stickler发育不良I型（STD-1）和Kniest发育不良（KND）。大多数COL2A1突变发生在α - 1（11）链的三螺旋区：SED谱主要归因于用大块氨基酸代替甘氨酸残基的错义突变，STD4归因于截断突变的单倍不足，KND归因于剪接位点突变导致的外显子跳变。为了进一步阐明11型胶原病变的基因型、表型关系，我们检测了56个疑似11型胶原病变家族的COL2A1突变，在41个家族中发现38个突变。所有22个错义突变和1个。三螺旋区域的帧缺失沿SED谱下降。甘氨酸到丝氨酸的替换导致交替区产生严重和温和的骨骼表型。甘氨酸到非丝氨酸残基的独家替换产生了更严重的表型。SED光谱的梯度不一定与骨骼外表现的发生相关。三螺旋或n -前肽区的9个截断或剪接位点突变均可引起STD-1或KND，并且在这两种表型中都不可避免地发生骨外改变。所有六个c -前肽突变产生一系列非典型骨骼表型，并产生眼部变化，而不是耳鼻喉部的变化。植物学报，26(1),2005。(c) 2005 Wiley-Liss, Inc。
Heterozygous mutations of COL2A1 create several clinical entities collectively termed type 11 collagenopathies. These disorders not only impair skeletal growth but also cause ocular and otolaryngological abnormalities. The classical phenotypes include the spondyloepiphyseal dysplasia (SED) spectrum with variable severity, Stickler dysplasia type I (STD-1), and Kniest dysplasia (KND). Most COL2A1 mutations occur in the triple helical region of alpha 1 (11) chains: the SED spectrum is mostly attributed to missense mutations that substitute bulky amino acids for glycine residues, STD4 to haploinsufficiency of truncation mutations, and KND to exon skipping due to splice-site mutations. To further elucidate the genotype,phenotype relationship of type 11 collagenopathies, we examined COL2A1 mutations in 56 families that were suspected of having type 11 collagenopathies, and found 38 mutations in 41 families. Phenotypes for all 22 missense mutations and one in. frame deletion in the triple helical region fell along the SED spectrum. Glycine to serine substitutions resulted in alternating zones that produce severer and milder skeletal phenotypes. Glycine to nonserine residue substitutions exclusively created more severe phenotypes. The gradient of the SED spectrum did not necessarily correlate with the occurrence of extraskeletal manifestations. All nine truncation or splice site mutations in the triple helical or N-propeptide region caused STD-1 or KND, and extraskeletal changes were inevitable in both phenotypes. All six C-propeptide mutations produced a range of atypical skeletal phenotypes and created ocular, but not otolaryngological, changes. Hum Mutat 26(1), 36-43, 2005. (c) 2005 Wiley-Liss, Inc.