The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene
The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene
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DOI：
10.1136/jmg.2005.035717
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发表时间：
2006-05-01
影响因子：
4
通讯作者：
Mortier, GR
中科院分区：
文献类型：
--
作者：
Hoornaert, KP;Dewinter, C;Mortier, GR
背景：大多数COL2A1错义突变是三螺旋结构域中的强制性甘氨酸残基的取代。只有少数非甘氨酸错义突变被报道，其中，精氨酸到半胱氨酸的取代占主导地位。目的：更详细地研究COL2A1基因精氨酸到半胱氨酸突变引起的表型。方法：对实验室检测到COL2A1基因精氨酸-半胱氨酸突变的所有患者的临床和影像学表型进行研究，并与异常基因型进行相关性分析。COL2A1基因分型采用DHPLC分析，随后对异常片段进行测序。结果：在11个不相关先证者中发现6种不同的突变（R75C、R365C、R519C、R704C、R789C、R1076C）。每个突变导致相当恒定和位点特异性表型，但从未观察到围产期致死性疾病。脊柱关节病患者身材正常且无眼部受累是R75C、R519C或R1076C突变患者的特征。第三和/或第四趾短是R75C突变的显著特征，而手指关节扩大的短指是R1076C替代的关键特征。在R704C突变的患者中观察到短指的Stickler发育不良。R365C和R789C突变分别导致典型的Stickler发育不良和先天性脊柱骨骺发育不良（SEDC）。结论：精氨酸到半胱氨酸的突变是相当罕见的COL2A1突变，导致一系列表型，包括经典的SEDC和Stickler发育不良，但也有一些尚未被识别和描述为II型胶原病的不寻常实体。
Background: The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate.Objective: To investigate in more detail the phenotype resulting from arginine to cysteine mutations in the COL2A1 gene.Methods: The clinical and radiographic phenotype of all patients in whom an arginine to cysteine mutation in the COL2A1 gene was identified in our laboratory, was studied and correlated with the abnormal genotype. The COL2A1 genotyping involved DHPLC analysis with subsequent sequencing of the abnormal fragments.Results: Six different mutations (R75C, R365C, R519C, R704C, R789C, R1076C) were found in 11 unrelated probands. Each mutation resulted in a rather constant and site-specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C, R519C, or R1076C mutation. Short third and/or fourth toes was a distinguishing feature of the R75C mutation and brachydactyly with enlarged finger joints a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C mutation. The R365C and R789C mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita (SEDC), respectively.Conclusions: Arginine to cysteine mutations are rather infrequent COL2A1 mutations which cause a spectrum of phenotypes including classic SEDC and Stickler dysplasia, but also some unusual entities that have not yet been recognised and described as type II collagenopathies.