Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus:: An extension of the Col4α1 allelic series and the identification of the first two Col4a2 mutant Alleles
Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus:: An extension of the Col4α1 allelic series and the identification of the first two Col4a2 mutant Alleles
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DOI：
10.1534/genetics.106.064733
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发表时间：
2007-02-01
期刊：
影响因子：
3.3
通讯作者：
Quintanilla-Fend, Leticia
中科院分区：
文献类型：
--
作者：
Favor, Jack;Gloeckner, Christian Johannes;Quintanilla-Fend, Leticia
基底膜对于适当的组织发育、稳定性和生理学是重要的。基底膜的主要成分包括层粘连蛋白和IV型胶原。IV型前胶原Col4a1和Col4a2形成异源三聚体[alpha 1（IV）]（2）[alpha 2（IV）]，其在早期发育阶段的基底膜中广泛表达。我们提出了9个Col4a1和3个Col4a2错义突变的遗传，分子和表型特征的随机诱变实验中恢复的小鼠。杂合子携带者在眼、脑、肾功能、血管稳定性和生存能力方面表现出缺陷。纯合子不能存活超过第二个三个月。10个突变导致胶原结构域内时间保守的Gly位点处的氨基酸取代，一个突变在羧基末端非胶原结构域中，并且一个突变在信号肽序列中并且预测破坏信号肽切割位点。尚未发现COL4A2突变的患者。我们认为在小鼠中观察到的自发性眶内出血是一种临床相关的表型，对识别COL4A1或COL4A2突变携带者具有相对较高的预测价值。
The basement membrane is important for proper tissue development, stability, and physiology. Major components of the basement membrane include laminins and type IV collagens. The type IV procollagens Col4a1 and Col4a2 form the heterotrimer [alpha 1(IV)](2)[alpha 2(IV)], which is ubiquitously expressed in basement membranes during early developmental stages. We present the genetic, molecular, and phenotypic characterization of nine Col4a1 and three Col4a2 missense mutations recovered in random mutagenesis experiments in the mouse. Heterozygous carriers express defects in the eye, the brain, kidney function, vascular stability, and viability. Homozygotes do not survive beyond the second trimester. Ten mutations result in amino acid substitutions at time conserved Gly sites within the collagenous domain, one mutation is in the carboxy-terminal noncollagenous domain, and one mutation is in the signal peptide sequence and is predicted to disrupt the signal peptide cleavage site. Patients with COL4A2 mutations have still not been identified. We suggest that the spontaneous intraorbital hemorrhages observed in the mouse are a clinically relevant phenotype with a relatively high predictive value to identify carriers of COL4A1 or COL4A2 mutations.